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TUBERCULIN    IN 
DIAGNOSIS    AND    TREATMENT 


Digitized  by  the  Internet  Archive 

in  2011  with  funding  from 

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Go  tbe  great  /iDasteu 
IRobert  Ikocb 


GERMAN    TUBERCULOSIS    CLASSICS 

Issued  on  the  advice  and  under  the  direction  of 
EGBERT    MORLAND,    M.D.,    B.Sc. 


TUBERCULIN    IN 
DIAGNOSIS    AND    TREATMENT 

A   Text=book   of   the    Specific    Diagnosis   and    Therapy 
of   Tuberculosis 

For    Practitioners    and    Students 


Dr.   BANDELIER  and                  Dr.   ROEPKE 

Medical   Director    of   Sanatorium  Medical   Director  of  the   Railway 

"  Schwarzwaldheim"  at  Schd7?iberg  Sanatorium      "  Stadtwald '  "       at 

(  Wildbad)  Melsungen  (  Cassel) 


SECOND    ENGLISH    EDITION 

Translated  from  the  Seventh  Revised  and  Enlarged 
German  Edition 

by 
WILFRED    B.    CHRISTOPHERSON 

With    Twenty-five  Temperature   Charts,  Two  Coloured  Lithographic  Plates, 
and  Five  Illustrations  in  the  Text 


NEW     YORK 

WILLIAM     WOOD     AND     COMPANY 

MDCCCCXIII. 


/3-  27^ 


^£3// 


Translator's  Note. 


>-  The    present    second    English    edition    of    "  Tuberculin    in 

Diagnosis  and  Treatment  "  is  a  translation  from  the  seventh 
German  edition  of  ihe  "  Lehrbuch  der  Spezifischen  Diagnostik 
und  Therapie  der  Tuberkulose."  Apart  from  the  addition  of 
side-headings,  the  omission  of  a  few  notes  unimportant  to  English 
readers  and  the  conversion  of  doses  from  cubic  centimetres  to 
cubic  millimetres  in  accordance  with  other  recent  English  text- 
books, the  work  has  been  translated  literally.  The  book  has  been 
rendered  into  English  on  the  basis  of  Dr.  E.  C.  Morland's 
translation  from  the  second  German  edition  (1909),  which  now 
forms  but  a  small  part  of  the  whole. 

I  acknowledge  with  many  thanks  the  valuable  assistance  of 
Dr.  E.  C.  Morland  in  the  translation  and  of  Dr.  G.  B.  Hunt 
in  the  revision  of  the  proof-sheets.  I  have  drawn  on  a  trans- 
lation of  the  sixth  German  edition  supplied  by  Dr.  D.  M. 
Barcroft.  The  publishers  of  the  German  edition — Messrs.  Curt 
Kabitzsch,  of  Wiirzburg — were  good  enough  to  send  me  their 
advance  sheets ;  by  this  means  the  translation  has  appeared  very 
shortly  after  the  publication  of  the  original. 

W.  B.  Christopherson, 

Laboratory  of  Clinical  Research, 

Arosa,  Switzerland. 
July,  1 913. 


Authors'    Preface. 


"  Tuberculin  in  Diagnosis  and  Treatment,"  four  years  after 
its  first  appearance,  has  reached  its  seventh  edition,  has  been 
translated  into  seven  foreign  languages,  and  the  English  and 
Russian  versions  are  now  in  their  second  edition.  This  success 
is  the  result  of  the  unanimous  and  hearty  appreciation  which 
has  been  accorded  to  the  several  editions  in  all  the  medical 
literature  at  home  and  abroad.  The  appearance  of  the  book  met 
a  very  real  need  and  the  form  in  which  it  was  presented  filled 
a  gap.  We  have  attempted  to  fulfil  the  last  wish  of  R.  Koch  with 
regard  to  the  subject  of  tuberculosis  and  tuberculin,  written  on 
May  12,  1909  :  "  To  maintain  the  same  high  standard  in  the  later 
editions  of  their  book  which  are  certain  to  follow."  This  hope 
of  the  master  could  not  be  dishonoured ;  it  made  the  work 
entailed  by  each  succeeding  edition  a  thankoffering  to  the  great 
physician  who  has  taught  us  to  recognize  tuberculosis  as  a 
popular  plague  and  to  treat  it  successfully. 

The  value  of  this  bequest  has  also  been  an  incentive  to  the 
enlargement  and  complete  revision  of  the  present  seventh  edition. 
Further,  various  critics  have  advised  certain  abridgments, 
enlargements  and  alterations.  One  objected  to  the  increasing 
size  of  the  book  and  feared  that  it  might  suffer  in  case  of 
reference  and  teaching  value  and  thereby  in  interest  for  details  of 
practical  importance ;  he  advised  more  rigid  treatment  of  matter 
and  of  the  views  of  other  authorities.  Another  critic  required,  in 
addition  to  all  details  of  theory  and  practice,  a  more  extensive 
treatment  of  certain  sections,  more  diagrams  to  illustrate  the  text, 
&c. — in  short,  enlargement  rather  -than  abridgment.  Then  came 
the  practitioners  demanding  by  mouth  and  pen  a  more  exact 
explanation  of  the  specific  processes,  of  the  nature  of  the 
tuberculin   reaction   and   the   healing  action   of  tuberculin. 

In  order  to  accede  to  all  justifiable  requests,  the  new  edition, 
which  had  in  the  meantime  become  necessary,  could  hardlv  be 
reduced  in  size;  on  the  contrary,  an  enlargement  was  unavoidable. 
In  order  to  restrict  this  to  definite  limits  and  not  to  hamper  the 
clear  description  of  specific  diagnosis  and  treatment,  all  matter 
relating  to  theory,  which  was  previously  scattered  in  the  various 


X  AUTHORS      PREFACE 

chapters,  has  now  been  collected  into  a  special  section,  completed 
and  condensed.  It  follows  the  introduction,  which  describes  the 
present  condition  of  tuberculosis  and  the  tuberculin  question. 
The  theoretical  section  leads  on  to  the  practical  conduct  of  the 
specific  diagnosis  and  treatment  of  tuberculosis.  In  describing 
the  theory  of  the  subject  we  have  had  to  be  short  and  concise, 
but,  in  spite  of  the  difficulties  entailed  by  the  numerous  views 
still  in  circulation,  we  hope  to  have  laid  a  foundation  on  which 
clinicians  and  practitioners  may  understand  and  conduct  modern 
tuberculin  treatment. 

The  specific  diagnosis  of  tuberculosis  has  remained  separated 
in  the  general  and  special  sections.  The  former  has  been  en- 
larged to  include  a  more  detailed  description  and  a  coloured 
illustration  of  the  intracutaneous  test,  the  latter  a  chapter  on  the 
specific  diagnosis  of  tuberculosis  of  the  digestive  organs  and 
some  new  charts  to  show  tuberculin  reactions.  In  both  sections 
the  literature  of  the  last  few  years  bearing  on  the  value  and 
province  of  tuberculin  diagnosis  has  been  critically  and  exten- 
sively noticed. 

We  have  made  more  important  changes  in  describing  the 
specific  treatment  of  tuberculosis.  In  the  first  place  parts  of  the 
general  and  special  sections  have  been  respectively  interchanged 
in  order  to  treat  one  of  the  most  important  chapters — that  dealing 
with  the  specific  treatment  of  pulmonary  tuberculosis — more 
clearly  and  convincingly.  In  addition  the  text  has,  on  the  one 
hand,  been  freed  from  many  unimportant  and  unsettled  details 
and,  on  the  other,  has  been  completed  by  the  inclusion  of  all 
important  advances  in  the  province  of  specific  therapy.  We  hope 
that  the  present  enlargement  is  free  from  omissions  and — apart 
from  our  own  experiences,  which  increase  from  year  to  year — 
describes  the  views  of  both  advocates  and  opponents  in  an  equally 
unbiased  manner.  We  have  only  left  undescribed  what  must 
appear  to  all  competent  judges  as  purely  superficial  and  irrational 
methods  of  treatment,   not  as  rational  tuberculin  therapy. 

In  the  general  section  dealing  with  specific  treatment,  chief 
attention  has  been  paid  as  before  to  the  most  trustworthy  of  the 
actively  immunizing  preparations.  All  other  known  preparations 
and  results  of  therapeutic  research,  according  to  their  present 
significance,  have  been  more  or  less  completely  or  summarily 
described  as  the  case  may  be.  We  should  have  considered  our- 
selves ill-advised  to  discuss  only  those  specific  remedies  in  very 
general  use,  tested  and  found  of  value,  and  to  reject  all  others. 
We  hope,  by  the  clear  division  of  matter  and  arrangement  of 
text,    to   have  considerably  allayed   the  fear  that  the   increasing 


authors'  preface  xi 

size  of  the  book  would  make  reference  a  matter  of  greater  diffi- 
culty. The  international  character  of  the  work  compelled  us  to 
make  it  no  mere  general  outline  but  a  genuine  text-book  which 
should  supply  to  every  reader  an  explanation  with  regard  to  any 
required  subject.  The  physician  should  be  able  to  afford 
information  on  any  specific  remedy  brought  to  his  notice  by 
advertisement;  and*  of  these  various  remedies  there  is  now  no 
small  number. 

In  the  special  section  of  specific  treatment  a  chapter  is 
added  dealing  with  tuberculosis  of  the  digestive  organs ;  all  other 
chapters  have  been  carefully  enlarged  in  accordance  with  present- 
day  knowledge,  the  several  organs  receiving  separate  treatment. 

In  the  enlarged  concluding  section  we  have  treated  the 
matter  from  the  standpoint  of  consistent  but  unbiased  positivism 
and  excluded  the  personal  note.  It  is  intended  to  convert  to  our 
views  the  opponents  of  specific  measures,  a  section  of  the  medical 
fraternity  becoming  smaller  and  smaller  but  not  yet  completely 
convinced,  and  at  the  same  time  to  encourage  the  diagnostic  and 
therapeutic  use  of  tuberculin  both  in  the  institution  and  in  general 
practice.  We  feel  justified  in  defining  and  fixing  its  sphere 
owing  to  more  than  ten  years'  work  in  the  specific  diagnosis  and 
treatment  of  tuberculosis  and  a  wealth  of  varied  personal  experi- 
ence inside  and  outside  the  sanatorium  which  can  hardly  have 
been  afforded  to  any  other  physician.  And  we  feel  it  our  bounden 
duty  to  aid  the  victorious  progress  of  tuberculin  through  all 
hospitals,  health  resorts  for  tuberculosis  and  sanatoria,  and  where 
its  valuable  action  will  be  displayed  in  a  still  higher  degree- 
through  the  ranks  of  the  practitioners. 

So  much  for  the  explanation  of  the  motives,  the  nature  and 
the  compass  of  the  present  revised  and  enlarged  seventh  edition. 
The  general  aim  of  the  whole  has  remained  the  same.  May  this 
volume  in  its  new  form  receive  a  kindly  reception  and  add  to 
the  friends  of  earlier  editions  fresh  champions  for  the  fight  against 
the  national  disease,  tuberculosis — with  the  aid  of  specific  diagnosis 
and  treatment. 

The  Authors. 

Melsungen  and  Schomberg, 
December,   191 2. 


ERRATUM. 

Page   9,    line    18    from    top,    for    "  clinicians,    Grace  "    read 
clinicians,  Grace." 


Robert    Koch's    Introductory    Note    to 
the   Third    Edition, 

It  gives  me  great  pleasure  to  accede  to  the  request  of  one  of 
the  authors  of  "  Tuberculin  in  Diagnosis  and  Treatment  "  that  I 
should  write  a  short  introduction  to  the  3rd  edition  of  this  work. 

In  my  first  publications  on  the  subject  of  tuberculin,  I  pointed 
out  both  the  diagnostic  and  therapeutic  value  of  this  remedy.  But 
for  a  long  time  tuberculin  failed  to  receive  the  consideration  due 
to  it  in  either  of  these  directions.  The  reason  was  obviously  that 
our  knowledge  of  how  to  attain  artificial  immunity  was  insuffi- 
cient, and  therefore  a  right  understanding  of  the  specific  effect  of 
the  remedy  and  the  extent  to  which  it  could  be  used  was  lacking. 
Consequently  results  were  expected  from  tuberculin  when  it  was 
no  longer  a  question  of  pure  tuberculosis  at  all,  but  of  mixed 
infections  with  exciting  causes  of  suppuration  and  of  influenza, 
then  widespread.  For  the  same  reason  the  fable  of  the  "  tubercle 
bacillus  rendered  mobile  "  was  believed  in,  and,  indeed,  if  I  am 
not  mistaken,  it  still  haunts  many  a  brain. 

Only  since  the  doctrine  of  immunity  has  been  more  and  more 
studied  and  understood  by  physicians  have  right  conceptions 
been  formed  as  to  the  method  of  applying  tuberculin  and  the 
nature  of  its  effect,  and  once  more  physicians  are  beginning  to 
turn  its  valuable  properties  to  good  effect.  This  change  of  opinion 
as  regards  tuberculin  has  been  largely  due  to  the  fact  that,  by  the 
use  of  the  Opsonic  Index  and  the  technique  for  the  Fixation  of 
Complement,  methods  were  found  which  made  it  possible  to  check 
the  effect  of  the  remedy,  whereas  before  a  purely  empirical  judg- 
ment had  to  be  formed.  Moreover,  the  splendid  successes  gained 
by  veterinary  surgeons  in  the  diagnosis  of  bovine  tuberculosis  and 
more  recently  the  v.  Pirquet  method,  which  has  so  extraordinarily 
simplified  the  diagnostic  use  of  tuberculin  in  the  treatment  of 
human  beings,  have  once  more  drawn  attention  to  tuberculin. 

From  all  quarters,  especially  from  abroad,  reports  are  now 
coming  in  of  scientific  research  work  dealing  with  the  specific 
treatment  of  tuberculosis.  In  the  first  place  it  was  the  specialists  in 
tuberculosis  who  made  use  of  tuberculin  treatment ;  but  now  that 
it  has  been  shown  that  tuberculin  can  also  be  used  with  advantage 


xiv  ROBERT    KOCH'S    INTRODUCTORY    NOTE 

and  without  any  danger  by  the  skilled  physician  in  private  prac- 
tice, it  would  appear  that  many  practitioners  are  desirous  of 
following  this  example.  But  there  is  an  obstacle  in  the  way, 
for  it  is  difficult  for  the  physician  who  does  not  happen  to  have 
an  opportunity  of  getting  the  requisite  information  from  a 
specialist  to  obtain  the  necessary  particulars  as  to  the  selection 
of  the  preparation  and  the  right  application  of  the  same.  For 
during  the  course  of  the  last  few  years  more  than  a  dozen  specific 
preparations  made  from  the  culture  fluid  of  the  tubercle  bacilli  or 
from  the  substance  of  the  bacilli  themselves  have  been  recom- 
mended for  the  treatment  of  tuberculosis,  and  it  is  obvious  that 
they  cannot  all  be  equally  valuable.  Moreover,  opinion  is  still 
very  much  divided  as  to  the  best  method  of  treatment.  And  as 
reports  on  the  various  preparations  and  on  the  methods  of  treat- 
ment are  widely  scattered  in  the  literature  of  the  subject,  some  con- 
siderable study  is  needed  to  form  an  opinion  on  the  present  con- 
dition of  the  specific  treatment  of  tuberculosis. 

Under  these  circumstances,  it  was  a  very  praiseworthy  task 
to  collect  and  consider  critically  all  that  is  known  of  the  specific 
diagnosis  and  treatment  of  tuberculosis  for  the  needs  of  the 
practitioner.  This  task  has  been  undertaken  by  Dr.  Bandelier 
and  Dr.  Roepke  and  most  skilfully  carried  out,  as  is  clearly 
proved  by  the  rapid  succession  of  the  editions  of  their  text-book. 
But,  apart  from  this,  I  have  satisfied  myself  that  this  latest  edition 
is  not  a  mere  compilation  of  extracts  from  the  literature,  but  a 
reliable  guide  for  all  those  who  wish  to  put  the  specific  treatment 
into  practice. 

I  should  also  like  to  draw  special  attention  to  the  fact  that  I 
agree  with  the  authors  that  when  specific  remedies  are  used  rise 
in  temperature  must  be  avoided  as  far  as  possible,  but  that  it  is  not 
advisable  continuously  to  give  only  the  smallest  doses,  as  recom- 
mended in  many  quarters.  It  must  not  be  forgotten  that  here  it 
is  a  question  of  active  immunization,  and  that  it  can  onlv  be  to 
the  advantage  of  the  patient  that  not  too  low  a  degree  of  immunity 
should  be  attained. 

I  should  like  to  state  that  I  also  agree  in  recommending 
specific  treatment  for  out-patients,  naturally  with  the  most  careful 
selection  of  cases. 

May  the  authors  maintain  the  same  high  standard  in  the 
later  editions  of  their  book,  which  are  certain  to  follow. 

R.  Koch. 

Berlin, 

May  12,   1909. 


Contents. 


Introduction 

I Theoretical    Part 

A.— THEORIES   OF    TUBERCULIN   REACTION 

i. — Changes  in  the  Toxin-sensitive  Cells 
2. — The  Toxin  Theory 

3. — The  Amboceptor   Theory  of  Wolff-Eisner 
4. — The  Theories  of  Hypersusceptibility  ... 
5. — The  Theory  of  Non-specific  Action  ... 

B.— THE  CURATIVE  FACTORS  OF  TUBERCULIN  ACTION 
1. — T  ox-immunity 
2. — The  Focal  Reaction 
3. — The  Antibodies  as  Curative  Factors 

(a)  Antitoxins    ... 

(b)  Agglutinins 

(c)  Opsonins 

(d)  Phagocytosis 

(e)  Bacteriotropins    and    Bacteriolysins 
(/)  Complement-nxing   Antibodies 

II. — The  Specific  Diagnosis  of  Tuberculosis  ... 

A.'— GENERAL   SECTION 

1. — The   Cutaneous   Tuberculin   Tests 

(a)  Cutaneous   Test  according  to  v.    Pirquet 

(b)  Percutaneous    Tuberculin   Test   of   Moro 

(c)  Intracutaneous    Tuberculin    Test 
2. — The  Conjunctival  Tuberculin  Test     ...• 
3. — The  Subcutaneous  Tuberculin  Test     ... 

B.— SPECIAL  SECTION 

1. — Tuberculin  Diagnosis  in  Tuberculosis  of  the  Lung  .. 
2. — Tuberculin  Diagnosis  in  Tuberculosis  of  the  Respira 

tory  Tract    ... 
3. — Tuberculin  Diagnosis  in  Tuberculosis  of  the  Digestive 

Organs  ...  ... 

4. — Tuberculin  Diagnosis  in  Urogenital  Tuberculosis 

5. — Tuberculin   Diagnosis  in   Tuberculosis   of  the   Serous 

Membranes    ...  ...  ...  ■ 

6. — Tuberculin  Diagnosis  in  Ophthalmic  Tuberculosis     .. 
7. — Tuberculin  Diagnosis  in  Aural  Tuberculosis  ... 
8. — Tuberculin  Diagnosis  in  Tuberculosis  of  the  Skin     .. 
9. — Tuberculin  Diagnosis  in  Tuberculosis  of  the  Glands 

Bones  and  Joints     ... 
10. — Tuberculin  Diagnosis  in  Children's  Diseases  ... 


page 


f3 
16 

18 
19 

2  2 

24 
24 
27 
28 
28' 
29 
30 
33 
35 
36 

37 
37 
38 
38 
49 
54 
58 
69 

93 
93 

106 


"3 


117 
n8 


123 


XVI  CONTENTS 

PAGE 

III. — The   Specific   Treatment   of  Tuberculosis             ...            ...  ...  129 

A.— GENERAL  SECTIOX         ...             ...             ...             ...  ...  129 

1,— General  Principles  of  Tuberculin  Treatment  ...  ...  132 

2. — Method  and  General  Technique  of  Modern  Tuberculin 

Treatment                   ...            ...            ...            ...  ...  139 

3, — The  Specific  Remedies  for  Tuberculosis         ...  ...  158 

[a)  Preparations  Designed  to  produce  Active  Immunity  ...  isg 

(1)  Old    Tuberculin    (AT)     ...              ...              ...  ...  159 

(2)  Albumose-free    Tuberculin    (AF)                ...  ...  164 

(3)  New   Tuberculin    (TR)    ...              ...              ...  ...  167 

(4)  New   Tuberculin   Baciliary   Emulsion    (BE)  ...  169 

(5)  Sensitized   Baciliary   Emulsion    (SBE)      ...  ...  173 

(6)  Landmann's   Tuberculoid.              ...              ...  ...  175 

(7)  The  Tuberculin  Preparations  of  Klebs  ...  ...  177 

(8)  Beraneck's    Tuberculin    (TBk)    ...             ...  ...  178 

(9)  Carl  Spengler's  Treatment  with  Bovine  Tuberculin  180 

(10)  Other  Tuberculins  on  the  lines  of  Koch  ...  ...  184 

(11)  Active  Methods  of   Immunization   on  the  lines  of 
Jenner   and   Pasteur        ...              ...              ...  ...  197 

(12)  Nastin    and    Tuberculo-Nastin    ...              ...  ...  205 

(b)  Preparations  designed  to  produce  Passive   Immunity...  208 

(13)  Maragliano'S    Serum        ...              ...              ...  ...  209 

(14)  Marmorek's    Anti-tubercular    Serum          ...  ...  211 

(15)  Hoechst   Tubercular   Serum          ...              ...  ...  214 

(16)  Streptococcus  Sera           ...             ...             ...  ...  216 

(c)  Vaccine    Treatment                  ...             ...             ...  ...  218 

[d)  Carl   Spengler's   Treatment  with   Immune  Blood  (IK)  218 

B.— SPECIAL  SECTION           ...             ...             ...             ...  ...  223 

—Pulmonary  Tuberculosis           ...            ...           ...  ...  224 

-Tuberculosis  of  tfie  Respiratory  Tract            ...  ...  234 

3. — Tuberculosis  of  the  Digestive  Organs             ...  ...  241 

4. — Tuberculosis  of  the  Urogenital  Organs           ...  ...  242 

-Tuberculosis  of  the  Serous  Membranes            ...  ...  249 

-Tuberculosis  of  the  Eye          ...           ...            ...  ...  250 

-Tuberculosis  of  the  Ear          ...            ...            ...  ...  257 

8. — Tuberculosis  of  the  Skin         ...           ...            ...  ...  257 

9. — Tuberculosis  of  the  Glands,  Bones  and  Joints  ...  261 

10. — Tuberculosis  in  Childhood      ...           ...           ...  ...  269 


/D 


Conclusion 

Literature                   ...  ...  ...             ...             ...             ...             ...     295 

Index                          ...  ...  ...            ...            ...            ...            ...     303 

Plates  and  Temperature  Charts. 


Introduction. 


Statistical  inquiries  as  to  the  causes  of  death  within  the 
German  Empire  have  shown  an  undoubted  decrease  in  mortality 
from  tuberculosis.  In  the  "  Medical  Statistics  of  the  Imperial 
Board  of  Health  "  the  following  figures  are  given  on  the  point: 
In  places  in  the  German  Empire  with  15,000  and  more  inhabitants, 
the  mortality  from  pulmonary  and  other  forms  of  tuberculosis 
amounted  in  the  year  1905  to  222*6  per  100,000  inhabitants;  in 
1906  to  2027  ;  1907  to  197*7;  I9°8  to  192*45;  1909  to  182*6;  and 
1910  to  177*8.  So  that  during  the  six  years  1905-1910  there  is  an 
unmistakable,  steady  and  considerable  decrease  in  the  numbers  of 
deaths  from  tuberculosis  among  the  urban  population  of  about 
300  of  the  largest  places  in  the  German  Empire. 

In  the  urban  and  rural  population  of  twenty  of  the  States  of 
the  German  Empire,  which  are  inhabited  by  more  than  97  per 
cent,  of  the  total  population  of  the  Empire,  there  died  from 
tuberculosis  per  100,000  inhabitants  :  In  the  year  1905,  205*7  (:79'7 
of  these  from  tuberculosis  of  the  lungs);  in  1906,  188*2  (162*9); 
in  1907,  184*3  (i59'6);  in  1908,  178*6  (154*  1) ;  in  1909,  169  (145*3); 
and  in  1910,  164  (140*5).  Here  also  there  is  an  appreciable 
decrease  in  the  last  three  years,  which  is  seen  still  more  clearly 
in  the  actual  figures:  1905,  120,338  deaths  from  tuberculosis; 
1910,  102,761  ;  therefore  about  17,500  fewer  victims.  Further, 
the  classification  of  these  deaths  according  to  the  age  of  the 
deceased  shows  that  tuberculosis  has  decreased  both  among 
persons  at  the  most  virile  time  of  life  and  amongst  children. 
Of  100,000  between  the  ages  of  15  and  60  there  died  of  pulmonary 
tuberculosis  in  1905,  237*6,  and  in  1910,  191*6;  between  the  ages 
of  1  and  15,  in  1905,  52*1  ;  in  1910,  36*1. 

In  Prussia,  according  to  the  "  Medical  Statistical  Informa- 
tion of  the  Royal  Prussian  Statistical  Authorities,"  there  died 
from  tuberculosis  in  1910,  60,479  people,  against  60,871  in  1909, 
63,320  in  1908,  and  65,054  in  1907.  The  figure  per  10,000  of 
population   for   1910  is  just  one  half  that  for   1878   (the  highest 

1 


2  TUBERCULIN   IN   DIAGNOSIS    AND   TREATMENT 

point),  and  is  the  lowest  yet  recorded.  The  decrease,  too,  in  the 
actual  number  of  deaths  (88,283  in  1886,  to  60,479  in  1910)  is  all 
the  more  noteworthy  in  view  of  the  increase  of  population  from 
twenty-eight  to  forty  million.  Tuberculosis  has  decreased  both 
in  the  country  (46  per  cent.)  and  in  towns  (48  per  cent.).  Of 
10,000  children  in  Prussia  between  the  ages  of  1  and  15  there 
died  from  tuberculosis  in  1876,  8-52  ;  in  1910,  7-34.  A  decrease  in 
infantile  mortality  from  tuberculosis  cannot  therefore  be 
recognized. 

Lastly,  a  comparison  of  the  number  of  deaths  from  tubercu- 
losis before  and  after  the  year  1905  gives  us  the  pleasing  informa- 
tion that,  after  an  increase  of  mortality  in  the  year  1905,  the 
death-rate  from  tuberculosis  in  the  German  Empire  has  now 
reached  the  minimum   of  all   observations. 

We  must  then  examine  the  causes  to  which  the  marked 
decrease  in  mortality  from  tuberculosis  during  the  last  four  years 
may  be  attributed.  For  in  previous  years  the  figures  for  tuber- 
culosis had  only  shown  slight  fluctuations,  and  in  1905  even  a 
slight  increase.  Undoubtedly  many  and  various  causes  are  here 
at  work,  and  to  go  into  all  these  would  overstep  the  limits  of  this 
introduction.  We  would  only  draw  general  attention  to  the  fact 
that  the  repeated  and  considerable  decrease  in  the  number  of 
deaths  from  tuberculosis,  which  previously  tended  to  remain 
stationary  or  even  to  increase,  coincides  in  point  of  time  and 
continues  concurrently  with  the  wider  adoption  of  the  specific 
treatment  of  tuberculosis.  Whether  this  is  the  real  cause  or  not, 
we  will  riot  at  present  discuss. 

But,  in  spite  of  this  decrease,  we  must  not  be  satisfied  and 
must  remain  convinced  of  the  necessity  for  further  prophylactic 
and  therapeutic  measures.  For  at  the  present  moment  in 
Germany  the  number  of  persons  suffering  from  tuberculosis  of 
the  lungs  is  still  to  be  estimated  at  about  three-quarters  of  a 
million,  and  in  Prussia  the  number  of  deaths  from  tuberculosis 
exceeds  the  total  number  of  deaths  from  typhoid,  diarrhoea,  small- 
pox, scarlet  fever,  diphtheria,  measles,  whooping-cough,  and 
puerperal  fever  by  50  per  cent.,  while  the  death-rate  from  tuber- 
culosis in  children  has  scarcely  shared  in  the  fall  of  the  total 
mortality  from  the  disease. 

It  appears  doubtful  whether  we  doctors  have  much  more  that 
is  new  and  important  to  say  to  the  general  public  in  order  to 
enlist  and  retain  its  services  in  all  classes  on  behalf  of  prophylaxis 
in  tuberculosis.  But  the  profession  itself  and  the  generation  of 
practitioners  now  growing  up  may  be  enabled  to  get  a  more 
hopeful  perspective  of  the  disease,  and  to  accomplish  more  than 


INTRODUCTION  3 

mere  symptomatic  treatment.  The  whole  modern  campaign 
against  disease  is  dominated  by  the  endeavour  to  improve  the 
methods  of  diagnosis  on  the  one.  hand,  and  to  make  them 
accessible  to  the  practitioner  on  the  other.  The  campaign  against 
tuberculosis  also  stands  or  falls  with  this  improvement  in  dia- 
gnostic method,  with  the  early  recognition  of  the  disease. 

We  must  therefore  pay  the  fullest  attention  to  every  prac- 
ticable extension  of  diagnostic  method,  all  the  more  as  there  is 
still  no  superabundance  of  available  and  trustworthy  means  for 
the  early  diagnosis  of  tuberculosis.  In  spite  of  all  the  progress 
made  during  the  last  two  decades,  tuberculin  is  still  the  sharpest 
and  finest  test  for  tuberculosis.  But  the  last  few  years  have 
given  an  entirely  different  aspect  to  the  specific  diagnosis  of 
tuberculosis,  although  the  optimism  with  which  at  first  the 
universal  value  of  local  tuberculin  tests  was  proclaimed  could 
not  be  maintained.  After  a  flood  of  publications,  a  broad  and 
sure  foundation  has  been  laid  from  which  basis  the  importance 
and  due  limitation  of  the  various  tuberculin  tests  can  be  defined, 
together  with  their  indications  and  contra-indications. 

We  are  free  from  that  conservative  standpoint  which  held 
fast  to  the  old  method — the  test  tuberculin  injection  of  R.  Koch 
— merely  because  of  its  age,  its  history,  and  its  proved  safety, 
though  in  diagnosis,  if  anywhere,  the  motto  holds  that  the  good 
must  not  be  lost  in  striving  to  attain  the  better.  It  is  from  this 
standpoint  that  we  have  worked  for  years  at  the  theory  and  practice 
of  the  treatment  of  tuberculosis.  We  have  made  numerous  com- 
parative experiments  to  test  the  various  methods  one  against 
another,  and  to  ascertain  the  limits  of  their  applicability. 

That  the  early  diagnosis  of  tuberculosis  is  of  the  greatest 
importance  from  a  hygienic  and  social  point  of  view  is  now 
recognized  by  doctors  and  public  officials  everywhere  and  is 
considered  as  a  fundamental  fact  confirmed  and  indeed  proved  by 
experience.  But  to  us  doctors  a  second  fact  is  evident,  namely 
that  the  timely  recognition  of  pulmonary  tuberculosis,  whose 
frequency  places  it  in  the  forefront  of  the  various  forms  of  the 
disease,  is  often  fraught  with  such  difficulties  that  physical 
diagnosis  alone  is  at  times  impossible  and  must  be  supplemented 
by  the  specific  methods  of  examination. 

Doubts  as  to  the  value  and  success  of  sanatoria,  which  are 
still  voiced  here  and  there,  can  only  be  satisfactorily  silenced  by 
indisputable  statistical  proofs.  In  the  first  place  it  must  be  proved 
that  the  patients  treated  in  the  sanatoria,  and  on  whom  the 
statistics  are  based,  are  all  suffering  from  tubercular  pulmonarv 
disease.     But   in   the   initial   stage   of   tuberculosis   this   proof   is 


4  TUBERCULIN   IN   DIAGNOSIS    AND   TREATMENT 

often  only  possible  by  means  of  tuberculin  diagnosis.  This  is 
true  in  a  still  higher  degree  in  the  case  of  tuberculosis  among 
children.  "  Only  by  the  employment  of  tuberculin  diagnosis  are 
we  able  to  distinguish  those  children  who  are  suffering  from 
tuberculosis  from  those  who  have  fortunately  escaped  this 
disease"  (Schlossmann,  Miinchener  med.  Wochenschrift,  1909, 
No.  8). 

The  earlier  tuberculosis  is  recognized,  the  more  easily  and 
certainly  is  it  curable.  Confirmation  of  this  statement  is  especially 
forthcoming  in  the  reports  of  the  principal  sanatoria.  Therefore 
the  Berlin  clinician  Kraus  considers  it  the  duty  of  practitioners  to 
make  the  fullest  use  possible  of  tuberculin  in  the  diagnosis  of 
cases  where  tuberculosis  is  suspected.  On  the  other  hand,  at  the 
Sixth  Annual  Congress  of  Sanatorium  Doctors  at  Diisseldorf  in 
191 1,  objection  was  taken  to  the  use  and  utility  of  tuberculin 
diagnosis  in  adults  in  ambulant  practice.  Our  belief  is  that  the 
demands  which  are  being  made  at  the  present  day  are  neglected 
or  under-estimated.  Tuberculosis  must  not  only  and  primarily 
be  diagnosed  in  adults,  but  also  in  children,  and  the  diagnostic 
use  of  tuberculin  by  the  subcutaneous  method  is  even  more 
urgently  needed  in  sanatoria  and  hospitals  than  in  ambulant 
practice.  Our  views  on  the  matter  were  clearly  voiced  by  Brecke 
at  the  same  Congress  :  "If,  as  is  demanded  by  the  fight  against 
tuberculosis  and  by  the  insurance  offices,  as  many  cases  as 
possible  shall  be  diagnosed  at  the  beginning,  Koch's  test  cannot 
be  dispensed  with"  (Third  Supplement  to  the  "  Beitrdge  zur 
Klinik  der  Tuberkulose  "). 

Those  connected  with  sanatoria  are  coming  more  and  more 
to  the  conclusion  that  if  not  merely  early  cases  of  pulmonary  tuber- 
culosis are  to  be  admitted,  but  cases  in  the  second  stadium,  or  even 
the  more  promising  cases  in  the  third,  and  permanent  results  are 
to  be  looked  for,  the  hygienic-dietetic  plan  of  treatment  must  be 
supplemented  in  some  way ;  and  it  seems  as  if  this  can  only  be 
done  successfully  by  means  of  specific  treatment.  Thus  the 
latest  reports  of  the  German  Central  Committee  for  the  Prevention 
of  Consumption  state  that  70  per  cent,  of  all  institutions  treating 
pulmonary  tuberculosis  employ  tuberculin.  For  the  real  public 
sanatoria,  Muttray  gives  the  figure  as  91  per  cent.  Some  doctors 
at  the  public  sanatoria  even  go  as  far  as  Ritter  and  prescribe 
specific  treatment  as  a  matter  of  routine  just  as  they  order  relative 
amounts  of  rest  and  exercise. 

Ritter,  in  his  sanatorium  at  Edmundstal,  first  selected  cases 
for  tuberculin  treatment  which  had  been  excluded  from  the  public 
insurance  institutions  as  being  in  too  advanced  a  stage  of  tuber- 


INTRODUCTION  5 

culosis,  or  which  had  already  undergone  treatment  without  avail 
The  results  in  these  cases,  which  were  far  better  than  in  those 
treated  without  tuberculin,  converted  him  and  made  him  an 
adherent  of  specific  therapy.  Ritter  therefore  holds  that 
sanatorium  physicians  are  not  merely  justified,  but  in  a 
certain  sense  bound,  "  to  make  the  widest  possible  use  of 
tuberculin  in  the  treatment  of  pulmonary  tuberculosis  " 
(Deutsche  med.  Wochenschrift,  1908,  No.  29).  A  purely 
objective  estimate  of  its  value  is  furnished  by  the  relative  num- 
ber of  tubercle  bacilli  in  the  sputum.  We  will  refer  to  the 
detailed  statistics  of  Bandelier,  Curschmann,  and  Lowenstein  in 
another  place.  Here  let  the  general  statement  suffice  that  under 
the  combined  sanatorium  and  tuberculin  treatment  at  least  twice 
as  many  patients  lose  their  bacilli  as  under  the  hygienic-dietetic 
treatment  alone.  Even  apart  from  the  slight  cases  where,  as 
Curschmann  rightly  states,  the  results  are  difficult  to  estimate, 
and  considering  only  the  results  in  the  third  stadium  with  and 
without  tuberculin,  the  figures  speak  clearly  enough  :  12' 1  per 
cent,  of  good  results  without  tuberculin,  37"8  per  cent,  with  tuber- 
culin, and  42"!  per  cent,  with  a  protracted  course -of  tuberculin. 
Curschmann  therefore  considers  it  quite  justifiable  to  treat  every 
suitable  case  with  tuberculin  from  the  first.  "  The  patient  is 
certainly  not  harmed,   and  he  may  reap  great  benefit." 

The  heads  of  private  sanatoria  in  increasing  numbers  are 
also  acknowledging  their  belief  in  the  use  of  preparations 
of  tuberculin  in  suitable  cases.  They  recognize  the  "  really 
definite  benefits  "  of  tuberculin  treatment,  and  acknowledge  the 
improved  results  in  the  treatment  of  progressive  phthisis  when 
tuberculin  is  added  to  the  hygienic-dietetic  method,  especially  as 
regards  loss  of  fever  and  bacilli  in  the  sputum. 

Philippi,  of  Davos,  noticed  that  in  cases  of  fever  treated 
specifically  72*2  per  cent,  lost  their  fever  :  of  patients  seriouslv 
ill  in  the  third  stadium,  70  per  cent,  lost  their  fever  with  tuber- 
culin, and  45*8  per  cent,  without  tuberculin.  Janssen  reports  from 
the  Deutsche  Heilstatte  in  Davos  extraordinarily  clear  cases  of 
loss  of  fever  due  to  tuberculin.  Our  own  results  are  recorded 
later. 

And  the  "financial"  supporters  of  the  treatment  of  tuber- 
culosis follow  the  physicians  in  their  appreciation  of  the  specific 
treatment.  Thus  the  public  insurance  office  at  Berlin  has  just 
fitted  up  a  building  for  treatment  with  tuberculin  where,  after 
dismissal  from  the  sanatoria,  insured  persons  who  are  still  not 
healed  may  get  periodical  out-patient  treatment  with  tuberculin 
until  they  are  finallv  cured.     This  combined  svstem  of  treatment 


6  TUBERCULIN   IN    DIAGNOSIS    AND    TREATMENT 

with  tuberculin  in  sanatoria  and  subsequent  ambulant  treatment 
has  been  worked  for  years  by  the  public  insurance  institutions  of 
West  and  East  Prussia  with  the  best  results.  It  has  now  also 
been  introduced  by  the  management  of  the  State  Railways  of 
Prussia  and  Saxony,  who  have  their  physicians  specially  trained 
in  the  specific  treatment  of  tuberculosis. 

Hospitals  and  infirmaries,  too,  in  which  tuberculin  prepara- 
tions have  hitherto  been  very  little  used,  are  tending  more  and 
more  to  make  use  of  specific  treatment.  We  will  quote  here  in 
the  first  place  the  words  of  Lenhartz,  who  proclaims  in  no 
uncertain  voice  the  new  era  of  tuberculin  for  hospital  practice  : 
"It  is  a  serious  omission  to  exclude  the  use  of  tuberculin  " 
(Discussion  on  Ritter's  paper,  read  before  the  Hamburg  Medical 
Association,  February  4,  1908).  v.  Leube  repeatedly  emphasized 
"  the  good  results  of  sanatorium  treatment,  especially  when  com- 
bined with  the  use  of  tuberculin  in  the  initial  stages  of  the 
disease  "  (Zeitschrift  f.  Tuberculose,  vol.  13,  No.  5). 

De  la  Camp,  whilst  laying  great  stress  on  hygienic-dietetic 
measures  inside  and  outside  the  sanatoria,  expresses  himself  in 
favour  of  tuberculin  therapy  extending  over  a  long  period  (Ses- 
sion of  the  Upper  Rhine  Doctors,  July  2,  1908).  And  according 
to  Schlossmann,  tuberculin  is  not  only  the  best  diagnostic,  but  also 
the  best  therapeutic  means  of  fighting  tuberculosis  in  children. 
Even  in  1909  Schlossmann  wrote  :  "  To-day  we  already 
undoubtedly  stand,  and  not  in  Germany  alone  " — as  the  two 
English,  two  French,  Italian,  Japanese,  Portuguese,  Russian, 
and  Spanish  translations  of  this  text-book  prove — "  in  the  midst 
of  a  new  era  of  the  specific  treatment  of  the  initial  stages  of  tuber- 
culosis ;  and  this  era  will,  in  my  opinion,  bring  to  tuberculin  the 
recognition  which,  much  to  the  prejudice  of  many  an  invalid, 
has  been  so  long  denied  it  "  (Deutsche  vied.  Wochenschrift, 
1909,  No.  7). 

More  were  won  over  to  this  opinion  by  an  inquiry  set  on  foot 
by  the  Medizinische  Klinik  in  1910,  as  to  the  "value  of  tuber- 
culin in  the  treatment  of  pulmonary  tuberculosis.  The  following 
extracts  from  the  answers  sent  in  by  individual  clinicians  clearly 
show  the  revolution  that  has  taken  place  in  the  opinion  held  as  to 
the  therapeutic  power  of  tuberculin.  (Med.  Klinik,  1910,  Nos. 
1,  5,  and  10.) 

Fr.  Kraus,  of  Berlin,  writes  :  "  In  the  first  place  it  must  be 
agreed  that  tuberculin  treatment  has  not  only  been  revived  here 
and  there,  but  is  being  universally  applied  in  general  practice. 
Tuberculin  treatment  must  not  become  the  affair  solely  of 
specialists." 


INTRODUCTION  7 

N.  Ortner,  of  Innsbruck:  "  I  have  never  ceased  to  use  old 
tuberculin  in  small  doses  and  in  carefully  increased  quantities, 
specially  in  afebrile  cases  of  initial  pulmonary  tuberculosis,  a 
proof  that  from  my  own  experience  I  considered  and  still  consider 
it  a  valuable  remedy  in  the  treatment  of  such  cases." 

Hirsch,  of  Gottingen  :  "With  all  three  kinds  of  tuberculin 
(Koch's,  Beraneck's,  and  Rosenbach's)  we  have  seen  good  results 
to  which  no  exception  could  be  taken,  in  a  series  of  carefully 
selected  cases,  and  with  very  circumspect  administration." 

v.  Leube,  of  Wiirzburg  :  "I  therefore  consider  the  treatment 
of  pulmonary  tuberculosis  with  small  doses  of  old  tuberculin  as  a 
therapeutic  measure  which  undoubtedly  favourably  influences 
and  effectively  assists  the  usual  treatment." 

Moritz,  of  Strassburg  :  "In  my  opinion  very  good  results 
mav  be  obtained  by  treatment  with  old  tuberculin.  (I  have  no 
experience  of  any  but  this  preparation.)  I  have  seen  good  results 
both  in  pulmonary  tuberculosis,  not  only  in  initial  but  also  in 
advanced  cases,  and  also  in  laryngeal  tuberculosis." 

Fr.  Miiller,  of  Munich  :  "  In  the  course  of  the  last  eighteen 
years  I  have  seen  a  whole  series  of  cases  of  tuberculosis,  in  which, 
after  treatment  with  tuberculin,  quite  striking  improvement  has 
taken  place  and  apparently  also  a  healing  of  the  tubercular 
disease.  I  am  speaking  not  only  of  tuberculosis  of  the  lungs,  but 
also  of  the  peritoneum,  the  urogenital  apparatus,  and  the  eye. 
These  results  have  led  me  to  use  tuberculin  very  widely  in  cases 
in  the  initial  stage  and  where  the  disease  is  not  very  far 
advanced." 

Heubner,  of  Berlin  :  "  On  the  other  hand  I  have  used  tuber- 
culin for  many  years,  always  in  small  doses,  in  the  glandular 
tuberculosis  incipiens  of  children.  Here  the  immediate  beneficial 
effect  of  a  careful  treatment  continued  for  about  two  months  both 
on  the  general  health  and  on  the  so-called  scrofulous  symptoms 
cannot  be  denied." 

v.  Stark,  of  Kiel  :  "In  some  cases  an  extraordinarily  good 
subjective  condition  was  noted  in  the  days  following  the  injec- 
tion, which,  in  children,  for  instance,  could  not  be  attributed  to 
the  influence  of  suggestion  ;  in  such  cases  objective  improvement 
also  took  place.  Harmful  effects  were  not  observed.  Without 
the  aid  of  tuberculin  we  get  splendid  results  in  initial  cases.  .  .  . 
Nevertheless,  I  would  not  like  to  give  up  using  it.  Its  administra- 
tion in  advanced  pulmonary  tuberculosis  is  permissible  if  used 
cautiously  and  with  careful  selection  of  cases,  and  sometimes 
gives  good  results." 

Schultze,    of    Bonn,    and    Soltmann,    of    Leipzig    are    more 


8  TUBERCULIN  IN  DIAGNOSIS  AND  TREATMENT 

reserved  as  regards  tuberculin,  if  not  inclined  to  reject  it.  The 
former,  in  consequence  of  very  good  results  from  the  use  of  tuber- 
culin in  tuberculosis  of  the  eye,  has  lately  taken  up  tuberculin 
treatment  again.  However,  he  reserves  his  judgment,  but  recom- 
mends a  more  extensive  treatment  of  surgical  tuberculosis  with 
tuberculin  as  very  desirable.  Soltmann  gives  his  experiences  in 
clinically  demonstrable  initial  pulmonary  tuberculosis  in  child- 
hood, in  which  with  very  small -ioses  of  old  tuberculin  he  had  no 
satisfactory  results.  For  the  rest  he  states  very  clearly,  "  I  do  not 
consider  myself  an  opponent  of  tuberculin  treatment." 

Only  Eichhorst,  of  Zurich,  after  experiments  with  Koch's  old 
tuberculin,  denies  that  there  is  any  favourable  healing  action 
even  at  the  very  commencement  of  tubercular  changes  in  the 
lungs  :  "  My  results  were  no  different  from  those  attained  without 
tuberculin  treatment  by  care  of  the  body,  good  food,  and  suitable 
residence  in  the  mountains,  or  even  by  a  rest  cure  in  an  institu- 
tion on  some  lower  level." 

In  answer  to  the  statement  of  Soltmann  and  Eichhorst  we 
should  like  to  say  that  on  the  one  hand  infantile  pulmonary 
tuberculosis,  when  it  is  clinically  manifest,  is  too  unfavourable  in 
prognosis,  and  on  the  other  hand  the  very  first  beginning  of 
tubercular  changes  in  the  lungs  in  the  case  of  adults  admit  of  too 
favourable  prognosis  for  it  to  be  possible  to  estimate  correctlv 
the  therapeutic  effects  of  tuberculin  by  them.  But  even  if  we 
only  count  the  verdicts  returned,  we  get  as  a  result  of  the  inquiry 
that  of  the  eleven  directors  of  university  clinics,  including 
children's  clinics,  eight  are  in  favour  of  tuberculin  treatment, 
only  one  against  it  and  two  undecided. 

This  also  corresponds  with  the  general  impression  made  by 
the  debate  on  "  The  Specific  Diagnosis  and  Treatment  of  Tuber- 
culosis "  at  the  Twenty-seventh  Congress  on  Internal  Medicine  at 
Wiesbaden  in  1910.  Penzoldt,  who  opened  the  debate,  declared 
himself  a  convinced  believer  in  tuberculin  diagnosis  and  therapy, 
and  in  the  course  of  the  discussion  Jochmann,  Petruschky,  Schloss- 
mann, Sahli,  Stintzing,  Ed.  Meyer,  Rothschild,  Jessen,  Meinertz, 
Burghardt,  Clemens,  Romberg,  and  others  did  the  same.  The 
Prague  clinician  v.  Jaksch  alone  expressed  himself  as  against  all 
employment  of  tuberculin,  because  there  was  absolutelv  no  certain 
proof  that  "tuberculin  has  a  specific  effect,"  and  because  the 
combination  of  hygienic-dietetic  treatment  with  the  climatic  in- 
fluence of  the  South  sufficed  to  cure.  We  are  of  opinion  that  there 
has  never  been  any  lack  of  strong  and  unmistakable  proofs  of  the 
specific  effect  of  tuberculin.  The  whole  of  the  first  tuberculin  era 
is  a  chain  of  proofs  that  its  specific  effect  was  too  powerful.     On 


INTRODUCTION  9 

the  other  hand,  the  treatment  of  such  a  disease  of  the  masses  by 
ordering  patients  to  the  South  would  meet  with  just  as  insuper- 
able difficulties  as  the  limitation  of  cures  to  high  mountain 
districts. 

Such  Utopian  proposals  only  serve  to  confirm  what  the 
president  of  the  Congress,  held  at  Wiesbaden  two  years  ago,  gave 
as  the  most  noteworthy  result  of  the  prolonged  debate  on  tuber- 
culin :  that  the  change  in  the  value  attached  by  clinicians  to 
tuberculin  was  very  apparent,  as  shown  by  the  proceedings  of  the 
Congress  on  Internal  Medicine  in  1891,  and  now  in  the  debates 
of  the  same  Congress  in  1910.  The  adhesion  of  quite  an  over- 
whelming majority  of  German  clinicians  to  the  claim  of  Koch 
for  a  specific  diagnosis  and  treatment  of  tuberculosis  is  an  accom- 
plished fact.  The  same  holds  good  in  other  countries;  we  will 
here  only  mention  the  warm  recommendation  of  tuberculin  treat- 
ment by  Doyen,  Mantoux,  Mayor,  Renon,  and  others  at  the 
Eleventh  French  Congress  of  Internal  Medicine  (Paris,  October 
13-15,  1910),  and  the  reports  of  the  English  clinicians,  Grace 
Calvert,  Eyre,  Butler-Harris,  Hewlett,  Carmalt  Jones,  Latham, 
Lawson,  Walters,  and  others.  Radcliffe's  statistics  state  that 
20  to  25  per  cent,  of  cases  lost  their  bacilli  with  clinical  treatment, 
50  per  cent,  with  combined  tuberculin  and  clinical  treatment 
(figures  which  exactly  correspond  to  observations  made  in  Ger- 
many). 

In  general  practice,  too,  the  time  is  past  when  the  mention 
of  tuberculin  was  taboo.  After  the  unhappy  experience  of  the 
first  tuberculin  era  of  1890-91,  with  its  unenlightened  and  mistaken 
method  of  administration,  it  certainly  seemed  advisable  to  leave 
specific  diagnosis  and  treatment  to  those  specially  concerned  with 
tuberculosis,  and  to  limit  its  application  to  the  sanatorium  ;  and 
even  later  than  this  the  question  was  rife  whether  it  was  advisable 
to  place  such  keen  weapons  as  the  specific  tuberculin  preparations 
in  the  hands  of  uninstructed  practitioners.  To-day  our  position 
must  be  a  different  and  a  wider  one.  The-specific  diagnosis  and 
treatment  of  tuberculosis  are  matters  which  have  been  closely 
investigated,  and  in  some  degree  settled,  since  the  value  and 
freedom  from  risk  in  the  administration  of  many  preparations  of 
tuberculin  are  well  recognized,  granted  correct  dosage  and 
selection  of  cases.  We  can,  therefore,  to-day,  without  fear  of 
catastrophes,  recommend  the  specific  treatment  of  tubercular 
disease  to  general  practitioners. 

If  we  aim  at  mastering  tuberculosis,  no  matter  by  what  means, 
the  struggle  must  in  the  future  be  fought  to  an  issue  within  the 
domain  of  the  general  practitioner.     At  present,  with   regard  to 


IO  TUBERCULIN   IN   DIAGNOSIS    AND    TREATMENT 

tubercular  patients,  the  practitioner  stands  in  an  unsatisfactory 
position  of  too  great  passivity. 

Non-specific  drug  treatment  has  failed,  and  can  only  bring 
amelioration  of  certain  symptoms  of  the  disease  without  stopping 
them  at  their  source,  even  though  any  number  of  new  and 
original  "cures"  are  put  on  the  market  by  enterprising  firms. 
The  same  applies  to  the  prescription  of  the  ordinary  six  weeks' 
treatment  at  baths  or  mineral  springs ;  and  the  hygienic-dietetic 
treatment,  which  produces  good  results  in  the  sanatorium,  meets 
in  practice  with  insuperable  difficulties  chiefly  on  social  and 
economic  grounds.  There  remain  the  remedies  with  specific 
action,  which,  just  because  they  do  act  specifically,  allow  no 
routine  prescription  and  application. 

Herein  lies  the  difficulty  for  the  busy  practitioner,  but  one 
which  can  in  truth  be  overcome  by  everyone,  since  it  should 
stimulate  him  to  make  out  of  the  practice  of  his  profession  what 
it  properly  should  be  :  an  art — the  art  of  helping.  Conflicts  of 
interest  are  not  to  be  feared  :  a  fact  of  some  practical  importance. 
It  will  fall  to  the  public  or  private  sanatorium  to  prepare  the 
tubercular  patient  by  means  of  the  hygienic-dietetic  course, 
physically  and  mentally,  for  specific  treatment,  to  initiate  this 
treatment  and  get  it  past  the  greatest  difficulties.  The  practi- 
tioner should  be  able  to  bring  to  a  successful  conclusion  at  home 
the  tuberculin  treatment  begun  in  the  sanatorium,  since  the  period 
of  treatment  in  the  sanatorium,  especially  in  the  more  severe 
cases,  does  not  suffice  to  attain  the  utmost  available  improvement. 
In  exceptional  cases,  one  may  be  able  to  dispense  with  the  after- 
treatment,  or  even  with  the  preliminary  sojourn  in  a  sanatorium. 

In  any  case  the  practitioner  should  become  vanguard  and  rear- 
guard in  the  campaign  against  tuberculosis  by  means  of  specific 
diagnosis  and  treatment,  and  be  able  to  follow  with  greater 
activity  and  satisfaction  the  fate  of  his  tubercular  clientele  than 
heretofore.  Most  important  of  all,  the  tubercular  patient,  thanks 
to  the  specific  diagnosis  of  the  practitioner,  would  reach  the 
sanatorium  in  good  time,  and  in  case  he  be  obliged  to  leave  again 
too  soon,  would,  thanks  to  specific  after-treatment,  be  really 
cured.  To  wait  for  further  experience  or  other  specific  remedies 
is  no  longer  necessary.  The  remedies  and  the  experience  we 
have,  and  the  patient  has  a  right  to  have  his  disease  recognized 
in  good  time,  and  so  to  be  timely  and  successfully  treated. 

It  is  a  question  whether  the  generality  of  practitioners  are 
ready  for  such  a  systematic  task,  but  the  signs  of  the  times  suggest 
it ;  and  it  is  well  that  it  is  so,  for  it  is  the  attitude  of  the  practitioner 
that  will  decide  whether  the  treatment  of  tuberculosis  is  to  remain 


INTRODUCTION  1 1 

a  common  object  of  practice  or,  outside  the  walls  of  the  sana- 
torium, be  confined  exclusively  to  the  consulting-room  of  the 
specialist. 

There  exists  the  need  of  accurate  and  good  instruction  in  this 
specific  method  of  diagnosis  and  treatment.  The  seventh  edition 
of  this  book  in  five  years  bears  witness  to  this.  Opportunity  to 
diagnose  and  treat  tuberculosis  with  tuberculin  is  certainly  at 
hand ;  for  the  student  in  his  university,  for  the  house-physician  in 
his  wards,  and  for  the  physician  in  his  practice.  But  the  highest 
degree  of  certainty  and  success  in  this  direction  will  only  be 
obtained  by  serious  study,  and  to  this  end  the  following  pages 
are  devoted. 


I.-  -Theoretical   Part. 


Experience  has  proved  the  victory  of  tuberculin  as  a  dia- 
gnostic and  therapeutic,  agent  in  the  fields  both  of  experimental 
research  and  of  clinical  investigation.  To-day  we  know  that  the 
original  conception  of  its  discoverer,  Robert  Koch,  of  the  nature 
of  tuberculin  action- and  reaction  was  based  on  a  false  foundation. 
The  failures  of  the  first  tuberculin  era  can  be  traced  to  this  miscon- 
ception. With  increased  knowledge  of  suitable  methods  of 
administration  and  with  the  improvement  of  results,  the  need  arose 
of  understanding  the  phenomena  which  occur,  of  explaining  the 
causes  underlying  them,  and  of  applying  the  knowledge  gained  to 
the  further  development  of  the  treatment.  Thus  in  course  of  time 
there  arose  a  number  of  theories  to  explain  the  action  of  tuberculin 
which  differ  from  each  other  in  many  and  important  details,  and 
of  which  many  are  still  unrefuted  and  unreconciled.  The  views 
as  to  the  explanation  of  the  elective  action  of  tuberculin  on  the 
tubercular  process  and  the  specificity  of  the  tuberculin  reaction  are 
especially  contradictory  and  different.  These  disagreements  are 
emphasized  by  sceptics  and  critics,  who  argue  that  they  go  to  prove 
the  absence  of  specificity  in  tuberculin  action.  In  discussing  the 
most  important  of  these  theories  we  must  acknowledge  that  we  still 
lack  a  really  satisfactory  explanation  of  the  physiological  events  in 
tuberculin  action.  But  we  hope  and  expect  to  interest  the  prac- 
titioner in  the  theory  of  the  subject,  because  it  helps  to  simplify 
and  deepen  the  understanding  of  many  a  clinical  fact  in  diagnosis 
and  treatment,  and  because  it  probably  forms  a  basis  starting  from 
which  future  research  will  reach  the  goal. 

The  most  important  theories  of  the  tuberculin  reaction  will  first 
be  discussed,  and  secondly  the  curative  action  of  tuberculin.  In 
this  we  shall  make  use  both  of  our  own  work  and  the  most  impor- 
tant results  of  research  in  the  study  of  immunity  [i].  In  the 
arrangement  of  the  matter  we  follow  the  method  of  F.  Meyer  [2]. 


THEORETICAL   PART  1 3 


A.-  -Theories  of  Tuberculin  Reaction. 


1.— CHANGES  IN  THE  TOXIN-SENSITIVE  CELLS. 

In    his    classical    studies    on    tuberculosis, 
Koch.  Koch  noticed  the  cellular  changes  following 

a  tubercular  infection.     He  writes   [3]  :  — 

When  a  healthy  guinea-pig  is  inoculated  with  pure  culture  of  tubercle 
bacilli  the  wound  usually  closes  up  and  seems  during  the  first  few  days  to 
heal  up.  But  in  about  ten  to  fourteen  days  there  appears  a  hard  nodule 
which  soon  breaks  down,  forming  an  ulcer  which  persists  till  the  death  of 
the  animal.  But  the  result  is  quite  different  when  an  already  tubercular 
animal  is  inoculated.  The  most  suitable  animals  are  those  which  have 
been  successfully  infected  some  four  to  six  weeks  previously.  In  such 
animals  the  wound  also  heals  at  first,  but  forms  no  nodule,  and  on  the 
following  or  second  day  peculiar  changes  take  place  at  the  site  of  inocula- 
tion; it  becomes  hard  and  assumes  a  dark  colour,  not  limited  to  the  site 
itself,  but  spreading  to  the  surrounding  tissue  to  a  diameter  of  o.  1  to  1.0  cm. 
During  the  next  few  days  it  becomes  clearer  and  clearer  that  the  changed 
skin  is  necrotic ;  it  is  eventually  shed  and  there  remains  a  flat  ulcerated 
area,  which  usually  heals  quickly  and  lastingly  without  infecting  the 
neighbouring  lymphatics. 

After   Koch  came  Buchner   [4],   who  came 
Buchner.  to  much  the  same  conclusions  as  we  hold 

to-day  :  — 

In  order  to  give  it  a  designation,  we  can  for  the  present  define  this 
condition  (after  recent  infection)  as  latent  irritation  caused  by  the  tubercle 
bacilli  present  in  the  body.  Of  the  latter  there  must  always  be  a  propor- 
tion which  encounter  unfavourable  conditions  for  life  and  will  degenerate 
and  die,  when  their  proteins  will  be  set  free  and  become  active.  The 
latent  irritation  caused  by  this  is  in  its  nature  not  a  passive  condition,  but 
the  expression  of  a  reaction  of  the  tissue  elements,  by  means  of  which  the 
latter  attempt,  although  unsuccessfully,  to  free  themselves  from  the 
exciting  cause  of  infection. 

Buchner,  too,  drew  attention  to  febrile  symptoms  as  a  sign 
of  tuberculin  reaction. 

Then  followed  the  further  observation  that  the  same  pheno- 
mena as  appear  after  the  re-injection  of  living  and  dead  bacteria 
can  be  produced  with  their  extracts — tuberculin.  R..  Koch  was 
again  the  first  to  give  details  of  this,  but  it  remained  for  the  later 
researches  in  immunity  to  separate  the  general  from  the  cellular 


14  TUBERCULIN   IN   DIAGNOSIS    AND  TREATMENT 

reactive  processes  in  the  general  changes  occurring  in  the  tuber- 
cular organism. 

,         The  greatest  notice,  although  criticism  was 
Wassermanns       both    favourable     and     unfavourable,    was 

Theory.  taken    of   Wassermann's    ingenious   theory 

of  the  occurrence  and  absence  of  the  tuberculin  reaction.  With 
the  help  of  fixation  of  complement,  Wassermann  and  Bruck  [5] 
succeeded  in  proving  the  presence  of  dissolved  products  of 
metabolism  of  the  tubercle  bacilli  and  of  their  antibodies  (anti- 
tuberculin)  as  reaction-products  in  extracts  of  tubercular  organs 
prepared  by  trituration. 

These  antibodies,  by  virtue  of  their  avidity  for  com- 
bination with  antigen,  extract  the  whole  quantity  of  tuberculin 
injected  from  the  blood  and  concentrate  it  in  the  tubercular  focus. 
In  the  union  of  the  antigen  (tuberculin)  with  its  antibody  (anti- 
tuberculin)  complement  is  fixed ;  consequently  there  takes  place  in 
the  tubercular  focus  an  increase  of  those  elements  (leucocytes, 
ferments)  which  possess  protein  digesting  properties,  leading  thus 
to  softening  of  the  tubercular  tissues. 

This  is  the  chain  of  events  in  a  tuberculin  focal  reaction ;  it 

is  usually  accompanied  by  fever,  which  is  then  the  result  of  the 

absorption  of  softened  tubercular  tissue. 

Christian  and        Wassermann's    theory    is    corroborated    by 

,_,  ,  1    .»  the  observations  of  Christian  and  Rosenblat 

Rosenblat  s  r_-.         _,    ,        ,    T  .        ,    , 

_  .  .  6  ,  at  Rubner  s  institute:   they  found  that 

Experiments  in  .    J  ,   ,  ,  .         ,  .  ,  '  ,  u 

~  in    tubercular    animals    which     have    been 

Hxation  ot  injected     with     tubercle-bacillary     prepara- 

Complement.  tions,  an  increase  of  antibodies  causing 
fixation  of  complement  and  simultaneously  a  rise  of  the 
agglutinating  power  of  the  blood  takes  place. 

While  the  agglutinins  of  tubercle  bacilli,  which  are  not 
identical  with  the  antibodies,  arise  in  the  normal  cells  of  the 
haematopoietic  organs,  the  complement  binding  ,"  tubercular  " 
antibody  is  exclusively  formed  in  tubercular  tissue.  The  occur- 
rence of  these  bodies  in  the  serum  does  not  produce  immunitv 
from  tuberculosis,  but  is  its  sign. 

This  agrees  with  the  fact  that  Wassermann,  Bruck,  Citron, 
Liidke,  R.  Kraus  and  others  also  proved  the  presence  of  antibody 
in  tubercular  patients  treated  with  tuberculin,  the  antibody  causing 
fixation  of  complement  in  the  serum  and  in  the  tubercular  foci. 

According  to  our  own  researches,  this  takes  place  frequently, 
but  not  always. 

.....  This  theory  explains   the   reduced   or  even 

obliterated   reactivity   of   the   tuberculinized 


THEORETICAL    PART  1 5 

organism,  in  spite  of  the  presence  of  the  disease  :  the  absence 
of  reaction  is  caused  by  the  fact  that  anti-tuberculin  is  present 
in  the  serum  and  arrests  the  tuberculin  before  it  can  reach  the 
focus  of  disease.  The  statements  of  Liidke  [7]  bear  this  out  : 
that  reactivity  to  injected  tuberculin  is  generally  maintained 
when  no  anti-tuberculin  can  be  found  in  the  serum,  and  that 
conversely  it  is  just  in  those  cases  where  anti-tuberculin  is  proved 
to  be  present  in  the  serum  that  the  tuberculin  injections  are  borne 
with  little  or  no  reaction. 

In  addition,  Bauer  [8]  found  in  his  research 
'  in  complement  fixation  in  children's  tuber- 

culosis that  with  the  appearance  of  a  fair  quantity  of  anli- 
tuberculin  in  the  blood,  the  reactivity  of  the  organism  to  cutaneous 
and  subcutaneous  tuberculin  decreased. 

In  tubercular  adults  the  antibody  causing  fixation  of  comple- 
ment also  appears  spontaneously,  i.e.,  without  previous  specific 
treatment,  in  the  serum  and  exudates.  Since  these  observations 
of  Wassermann,  Citron,  Bruck,  Liidke,  Michaelis,  Leonor,  and 
Wolff-Eisner  were  made  chiefly  on  cases  with  severe  lesions  and 
miliary  tuberculosis,  the  absence  of  reaction  to  subcutaneous 
tuberculin  in  advanced  cases  is  also  intelligible.  Antigen  and 
antibody  may  unite  in  the  serum  and  cause  the  neutralization 
of  the  tuberculin  to  take  place  in  the  blood,  not  in  the  diseased 
tissues ;  thus  both  local  reaction  in  the  focus  of  disease  and 
general  reaction  are  prevented.  But  even  in  cases  not  so  far 
advanced,  the  "tuberculin-neutralizing  antibodies"  act  upon  the 
"  hypersensitizing  substance  "  and  tend  to  prevent  a  tuber- 
culin reaction.  On  this  depends  the  necessity  of  individualizing 
the  doses  of  tuberculin  used  for  diagnostic  purposes. 

~.  .     ..  The  researches  of  Wassermann  and  Bruck 

Objections  to  .   .    .    ,  .,-,,. 

...  ,         and  their  bearing  on  the  action  of  tuberculin 

Wassermann  s       .  .  ■      ,  .         ,      TTr 

have  not  remained  uncontested.     We  may 

Theory.  refer  to  tne  objections  of  Weil  and  Naka- 

jama  [9]  and  Morgenroth  and  Rabinowitsch  [10],  which,  how- 
ever, seem  in  the  main  unsound.  The  doubts  they  express  as 
to  the  specificity  of  the  antibodies  in  particular  are  shown  to 
be  unjustified  by  the  serological  investigations  of  Engel  and 
Bauer  [11]  on  children  at  the  Diisseldorf  Academy.  Thev 
never  found  spontaneous  antibodies  in  the  blood  of  a  tubercular 
suckling  or  young  child — in  contradistinction  to  the  adult 
phthisical  patient — never  in  healthy  children,  and  never  in 
cases  of  syphilis  and  pneumonia.  On  the  other  hand,  anti- 
bodies were  produced  in  the  blood  of  all  tubercular  children 
by    the    injection    of    tuberculin,    which    attained    the    maximum 


1 6  TUBERCULIN   IN   DIAGNOSIS   AND   TREATMENT 

with  the  quantity  of  tuberculin  injected,  and  after  cessation  of 
the  injections  disappeared  again,  first  rapidly,  then  more  slowly. 
From  these  facts  we  see  that  we  are  dealing  with  a  specific 
deviation  of  complement,  i.e.,  with  specific  antibodies  to  tuber- 
culin, as  Wassermann  and  Bruck  have  maintained  from  the  very 
first.  The  substitution  of  the  term  "anti-tuberculin  "  for  "anti- 
body producing  fixation  of  complement,"  is  quite  immaterial; 
it  is  also  immaterial  that  the  amount  of  anti-tuberculin  and  the 
susceptibility  to  tuberculin  do  not  necessarily  run  parallel.  The 
specificity  of  the  antibodies  in  tuberculosis  is  also  proved  beyond 
dispute  by  other  authors,  recently  by  Llidke  and  Sturm  [12], 
who  both  obtained  diagnostic  reactions  in  tubercular  patients 
only  by  means  of  tuberculin  preparations,  never  with  extracts  of 
streptococci,   typhoid,   dysentery,   or  colon  bacilli. 

_.,        ,  Citron    [ii~\    has    somewhat    modified    and 

Citron's  ,     L , OJ  w  ,         ,  TJr 

completed       Wassermann  s      theory.        He 

Modi  ication.  assumes  that  in  the  tubercular  focus  there 
are  toxin-sensitive  cells,  which,  by  the  injection  of  small  doses 
of  tuberculin,  become  rich  in  receptors  (sessile  receptors).  The 
latter  attract  the  injected  tuberculin,  produce  the  reaction,  and 
are  finally  disposed  of  in  the  blood.  Besides  these  cells  in  the 
foci,  Citron  holds  that  also  all  other  cells  in  contact  with  tuber- 
culin form  these  specific  receptors,  which  are  shed  into  the  blood- 
stream. Thus  in  many  cases,  instead  of  neutralizing  the 
tuberculin,  they  may  produce  hypersusceptibility  to  tuberculin  ; 
and  this  hypersusceptibility  increases  with  the  number  of  sessile 
receptors  in  the  focus.  Citron  has  also  proved  that  such  sera 
in  conjunction  with  tuberculin  and  complement  kill  guinea-pigs. 
Thus  the  occurrence  of  hypersusceptibility  to  tuberculin  after 
repeated  injection  of  small  doses  is  explained. 

According  to  Pappenheim  [14],  neither  the 
appen  eim.  £ree  nQr  ^e  sessile  receptors  produce  the 
phenomena  of  the  tuberculin  reaction,  which  are  caused  by  the 
fresh  formation  of  these  receptors  due  to  the  tuberculin  injection. 
According  to  this,  the  tuberculin  reaction  would  be  simply  the 
active  "anti-reaction  "  of  the  organism. 


Koch. 


2.— THE  TOXIN  THEORY. 

The  first  to  explain  the  tuberculin  reaction 
as  a  toxic  action  was  R.  Koch  [3]  himself. 
According  to  his  original  description,  tuberculin  produced  deep- 
rooted  changes  in  the  nutrition  of  the  tubercular  tissue,  causing 
its  destruction.  The  toxic  process  is  accompanied  by  fever 
and  general   reaction.     On   healthy   people,    the  toxin   only   acts 


THEORETICAL    PART  I  7 

in  relatively  large  doses.  The  same  was  found  in  animal  experi- 
ment :  0.5  c.c.  old  tuberculin  kills  a  tubercular  guinea-pig,  while 
a  healthy  animal  tolerates  this  dose  without  reaction.  Thus 
Koch  saw  in  tuberculin  a  true  toxin,  which  by  injection  in  slowly 
increasing  doses  is  capable  of  producing  immunity.  When  the 
doctrines  of  immunity  were  subsequently  revised  and  extended, 
he  changed  his  ideas,  inasmuch  as  he  considered  tuberculin 
treatment  an  active  immunizing  process. 

Almost   greater   attention   was   paid  at   the 
Hertwig.  time  of  its  description   to   Hertwig's  toxin 

theory,  which,  influenced  by  Metchnikoff's  phagocyte  teaching, 
explained  the  tuberculin  reaction  as  a  primary  focal  reaction  pro- 
duced by  a  chemotactic  influence  of  the  leucocytes.  Hertwig  [15] 
based  his  theory  on  Stahl  and  Pfeffer's  laws  of  chemotaxis ;  he 
considered  that  the  leucocytes  of  a  tubercular  organism,  by  virtue 
of  the  continual  production  of  toxin  in  the  foci,  became  tolerant 
of  the  tuberculin,  and  that  after  an  injection  of  tuberculin  a 
positive  chemotactic  irritation  is  exerted  on  the  leucocytes  pre- 
viously at  rest  owing  to  the  increased  concentration  of  the  tuber- 
culin. This  influx  of  leucocytes  causes  the  focal  reaction,  on 
which  the  febrile  and  general   reaction   is  dependent. 

Ehrlich   [16]    localized  the  reaction   in   the 

middle  of  the  three  cell  layers  which  en- 
circle the  tubercular  focus  like  the  layers  of  an  onion.  While 
the  central  caseated  and  the  adjoining  normal  tissues  were  un- 
damaged by  tuberculin  and  insensitive  to  the  toxin,  the  inter- 
mediate zone,  damaged  by  the  toxins  of  the  bacilli,  was  specially 
capable  of  reaction.  The  production  of  specific  antibodies  took 
place  in  these  toxin-sensitive  cells ;  and  the  production  of  anti- 
bodies was  the  essential  part  of  the  mechanism  of  the  reaction. 

Of  late  the  standpoint  has  been  increasingly 

Tuberculin  a         taken  up  that  tuberculin  is  a  primary  toxin 

Primary  Toxin  for  for  the  tubercular  organism,  chiefly  because 

the  Tubercular      there    is    no   proof    of    the   presence    of   an 

Organism.  anaphylactic    reactionary    body,    either    by 

a  serum  reaction  or  by  transference 
of  hypersusceptibility  (R.  Kraus,  Lowenstein,  Volk,  and  others). 
It  is  now  generally  considered  that  there  circulates  in  the  tubercu- 
lar organism  a  hypothetical  antibody — Wassermann  calls  it  anti- 
tuberculin,  Wolff-Eisner  an  albuminolytic,  Sahli  a  bacteriolytic 
amboceptor,  Citron  a  sessile  receptor— which  changes  the  tuber- 
culin, inert  in  itself,  into  a  highly  toxic  substance.  On  this  basis 
the  tuberculin  reaction  is  explained  by  assuming  that  the  tuber- 
culin set  free  in  the  focus  first  causes  hyperemia — focal  reaction — 
2 


1 8  TUBERCULIN   IN   DIAGNOSIS   AND  TREATMENT 

and  from  the  resulting  general  intoxication  the  general  reaction 
follows. 

That  tuberculin  is  a  primary  toxic  tubercle  "  poison  "  is 
proved  by  the  action  of  Landmann's  [17]  Tuberculol,  of  which 
a  dose  of  1  c.c.  kills  a  healthy  guinea-pig  of  250  grm.  weight. 
But  tuberculin  differs  from  the  true  primary  toxins  in  that  it  is 
unable  to  cause  formation  of  antibodies  in  a  healthy  organism. 
Nevertheless,  the  idea  of  a  primary  toxic  action  to  explain 
tuberculin  reaction  is  justified,  as  Pickert  [18]  and  Lowenstein 
[19]  proved  in  the  serum  of  tubercular  patients  treated  with  old 
tuberculin  the  presence  of  specific  substances  (anticutins)  which 
neutralize  the  action  of  tuberculin  on  the  skin.  The  nature  of 
these  anticutins  is  at  present  quite  unknown  ;  their  presence  was 
also  proved  by  Hamburger,  v.  Monti,  White,  Graham,  and 
others.  It  is  certain  that,  in  addition,  other  antibodies  may  arise 
after  tuberculin  injections.  Ruppel  and  Rickmann  [20]  have 
proved  that  the  serum  of  immunized  animals  not  only  neutralizes 
tuberculin,  but  even  renders  tubercle  bacilli  non-toxic.  And 
quite  lately  Abderhalden  has  shown  that  blood-plasma  of  tuber- 
cular patients,  in  contrast  with  that  of  normal  individuals,  can 
decompose  peptone  extracted  from  tubercle  bacilli. 

--                  ,  While    Hertwig    explained    the    tuberculin 

ivieyer  and  .                 .       ,              .     .              ...           r 

.  reaction    on   the   basis   of   the   condition    of 

Schmitz.  the  ieucocyteSj    p.   Meyer  and  K.  Schmitz 

[21]  have  recently  found  in  the  red  blood  corpuscles  of  tubercular 
animals  a  reactionary  body,  which,  after  corresponding  com- 
bination with  tuberculin,  forms  toxic  substances.  These  authors 
explain  the  tuberculin  reaction  as  follows  :  The  injected  tuber- 
culin is  taken  up  by  the  erythrocytes  and  carried  to  the  focus, 
where  the  first  and  strongest  receptors  for  tuberculin — the  anti- 
tuberculin  of  Wassermann — are  found.  These  receptors  exert,  after 
the  injection,  a  great  attractive  irritation  on  the  blood  corpuscles 
containing  tuberculin  and  thus  cause  the  hyperasmia  of  the  focus 
and  the  focal  reaction.  Simultaneously  the  toxin  set  free  by  the 
union  of  receptor  with  tuberculin  causes  the  general  reaction. 
The  repeated  injection  of  small  amounts  of  tuberculin  leads  to 
the  formation  of  increasing  quantities  of  toxin,  to  which  the 
body  replies  with  insensitiveness,  possibly  brought  about  by 
formation  of  the  antitoxins. 

3.— THE  AMBOCEPTOR  THEORY  OF  WOLFF-EISNER. 

Wolff-Eisner  [22]  modified  Wassermann's  observation  by 
substituting  for  tuberculin  the  bacterial  bodies  or  the  fragments  of 


THEORETICAL    PART  1 9 

them  contained  therein,  and  for  the  antibodies  (anti-tuberculins) 
the  bacteriolysins  present  in  alL  subjects  of  tubercular  infection. 
The  fragments  of  bacilli,  as  such,  produce  no  result  :  the 
simultaneous  presence  of  bacteriolysins  "  unlocks  "  them,  setting 
free  the  potent  substances  they  contain,  and  these  act  on  the 
diseased  focus  and  the  body  as  a  whole,  producing  the  tuberculin 
reaction.  In  this  connection  hypersusceptibility  plays  a  marked 
role.  On  it  depends  the  mobilization  of  the  bacteriolytic  powers 
of  the  body,  the  condition  of  hypersusceptibility  at  the  particular 
moment  governing  the  grade  of  toxin  production  and  absorption. 
According  to  Zieler  [23],  however,  the 
e  er"  idea  of  insoluble  corpuscular  fragments  of 

bacilli,  even  if  ultramicroscopic,  to  explain  the  action  of  tuber- 
culin is  untenable,  since  the  dialytic  products  of  tuberculin  have 
the  same  action  as  old  tuberculin  and  bacillary  emulsion.  There- 
fore the  assumption  of  bacteriolysins  for  the  occurrence  of 
tuberculin  action  is  untenable.  Wolff-Eisner  has  now  extended 
his  conception,  inasmuch  as  he  now  considers  that  the  lytic  ambo- 
ceptors not  only  dissolve  the  bacilli,  but  also  decompose  the  toxic 
bacterial  proteins  arising  from  them ;  the  bacteriolysins  are  also 
albuminolysins. 

Sahli    [24]    agrees   in    general   with   Wolff- 
Eisner;    he    considers   the    lysinized    tuber- 
culin an  active  antigen,   forming  secondary  endotoxin.     On  the 
F    M  other  hand,   F.   Meyer  [2]   demands,   for  a 

yer"  satisfactory  interpretation  of  Wolff-Eisner's 

theory,  the  proof  of  the  lytic  amboceptor  in  the  serum  of  tuber- 
cular patients  and  the  definite  passive  transference  of  hyper- 
susceptibility. But  the  experiments  of  Ruppel  already  mentioned 
show,  in  opposition  to  these  demands,  that  a  tubercular  serum 
with  bacteriolytic  properties  is  able  to  annul  tuberculin  action, 
not  to  increase  it.  Also  the  distinctly  decreased  power  to  cause 
reaction  of  sensitized  tubercle  bacilli  in  tubercular  individuals 
speaks  against  the  lysin  theory,  as  on  the  latter  the  sensitization 
would  cause  considerably  stronger  reactions. 

4.— THE  THEORIES  OF  HYPERSUSCEPTIBILITY. 

The  conception  of  hypersusceptibility  is  ascribed  to  v. 
Behring,  but  specific  hypersusceptibility  was  first  established  by 
Koch  himself  by  the  discovery  of  two  facts  :  (1)  That  tubercular 
guinea-pigs  reply  to  a  second  infection  by  tubercle  bacilli  with 
necrosis  and  shedding  at  the  place  of  inoculation,  and  (2)  that  only 
the  tubercular  organism  exhibits  a  typical  reaction  to  tuberculin. 


20  TUBERCULIN  IN   DIAGNOSIS   AND   TREATMENT 

Kretz  [25]  then  proved  that  a  normal  animal  does  not  reply  to  the 

injection  of  an  equilibrized  mixture  of  toxin  and  antitoxin  with 

the   formation    of    antitoxin,    while   a   previously   treated   animal 

reacts  to  the  same  injection  with  a  copious  production  of  antitoxin. 

In  consideration  of  this  fact,  Lowenstein  and  Rappaport  [26]  were 

induced  to  test  the  same  chain  of  ideas,  using  tuberculin.     By  the 

repeated    injection    of    the    smallest    doses    of    tuberculin,    they 

succeeded   in   artificially  producing  a   hypersusceptibility   of  the 

organism  to  tuberculin. 

_..  ,,  v.  Pirquet  [27!  coined  the  word  "  allergie  " 

v.  Pirquet  s  .         .  .  . 

to  describe  a  changed  capacity  for  reaction 

Allergia.  ^^   »pyeta^       Tnis    idea    of    allergia    has 

also  been  applied  to  the  tuberculin  reaction.  Just  as  in 
animals  which  have  undergone  previous  treatment  with  protein, 
so  in  the  tubercular  subject  there  is  an  allergical  action  against 
the  bacterial  protein.  Thus  the  cutaneous  tuberculin  reaction 
also  depends  on  allergia,  i.e.,  on  the  altered  reaction  which  the 
organism  gives  to  the  infecting  agent,  already  known  to  it. 
The  person  inoculated  for  the  second  time — or  the  tubercular 
individual — reacts  in  point  of  time,  quality  and  quantity  differently 
from  one  inoculated  for  the  first  time — or  the  non-tubercular." 

As  long  ago  as  1903,  v.  Pirquet  and  Schick  had,  on  the  occasion  of  the 
discussion  at  the  Gesellschaft  fur  Kinderheilkunde  (Cassel,  1903),  ex- 
pressed the  view  that  the  capacity  of  the  tubercular  patient  to  react  to  tuber- 
culin, of  the  vaccinated  subject  to  vaccine,  and  of  the  animal  inoculated 
with  horse-serum  to  serum,  were  all  conditioned  by  "  reaction-products  of 
the  nature  of  antibodies."  Further  clinical  investigations  on  the  various 
forms  of  reaction  to  ordinary  vaccine  lymph  led  v.  Pirquet  to  the  observation 
that  reaction  only  occurred  within  twenty-four  hours  in  the  case  of  pre- 
viously vaccinated  subjects,  and  that  this  capacity  of  "  vaccinal  early 
reaction  "  begins  during  the  febrile  period  of  vaccination  and  lasts  several 
years. 

An  entirely  analogous  reaction  of  hypersusceptibility  of  the  skin 
(allergie)  he  observed  to  occur  when,  in  the  tubercular  subject,  a  small 
quantity  of  tuberculin  was  applied  cutaneously.  At  the  spot  there 
developed  in  the  skin  a  reaction  remaining  localized,  an  inoculation  papule, 
also  based  on  the  principle  of  the  vaccinal  early  reaction  and  conditioned 
by  the  coming  together  of  toxin  (tuberculin)  and  antibody.  The  presence 
of  antibody  demonstrated  by  the  reaction  affords  proof  of  the  existence  of  a 
previous  or  still  active  tubercular  infection  in  the  inoculated  organism. 
This  is,  in  its  main  features,  the  line  of  thought  which  led  v.  Pirquet  to 
the  diagnostic  application  of  allergia  in  tuberculosis. 

The  latest  theory  of  hypersusceptibility  is 

Friedberger.         Friedberger's  theory  of  anaphylaxis.     The 

word    "  anaphylaxis  "    introduced   by    Richet    is   applied   to   the 


THEORETICAL    PART  21 

phenomenon  of  hypersusceptibility  which  occurs  after  injection 
of  solutions  containing  foreign  protein,  discovered  by  v.  Behring 
some  time  previously.  The  change  of  terminology — hypersuscep- 
tibility to  anaphylaxis — is  rather  unfortunate;  for  anaphylaxis 
denotes  lack  of  protective  power,  while  hypersusceptibility  is 
almost  the  exact  reverse.  Friedberger  [28]  considers  the  hyper- 
susceptibility the  result  of  the  anaphylatoxin  arising  by  the  action 
of  antibodies  from  the  foreign  protein  injected.  According  to 
his  view,  the  tuberculin  reaction  takes  place  as  follows  :  The 
antibodies  formed  by  the  tuberculin  injection  set  free  toxin  from 
the  tubercle  bacilli  in  the  focus,  which  cause  the  focal  and 
general  reaction.  This  hypothesis  of  hypersusceptibility  to  tuber- 
culin is  disputed  by  some  authors.  Thus  Bessau  holds  that  it  is 
bound  up  with  the  tubercular  inflammation,  while  the  condition  of 
reduced  susceptibility  to  tuberculin  is  "  non-specific  "  and  to  be 
considered  as  "  anti-anaphylactic."  We  hold  that  the  lasting 
insusceptibility  of  specifically  treated  patients  is  an  argument 
against  Bessau's  interpretation  and  proves  its  real  nature — a 
phenomenon  of  immunity.  Friedberger  and  his  co-workers  object 
to  the  technique  of  Bessau's  experiments,  in  which  the  specific 
anti-anaphylaxis  is  only  partially  masked  by  non-specific  resis- 
tance and,  in  a  series  of  important  researches  [29],  bring  forward 
new  experimental  proofs  which  still  further  establish  the  doctrine 
of  the  specificity  of  anti-anaphylaxis. 

Further  objections  have  been  made  against 

Objections.  t^e  theories  which  give  hypersusceptibility 

as  the  cause  of  the  tuberculin  reaction,  of  which  the  most  impor- 
tant is  that  which  urges  that  the  passive  transference  of  hyper- 
susceptibility to  tuberculosis  in  man  or  guinea-pig  has  hitherto 
proved  impossible.  Our  own  experiments  in  this  direction  have 
also  all  been  negative.  However,  we  ought  not  summarily  to 
reject  the  connection  between  the  tuberculin  reaction  and  protein 
anaphylaxis.  It  is  doubtless  present  in  allergia  in  the  sense 
of  v.  Pirquet,  so  that  it  can  onlv  be  concluded  that  the  sub- 
cutaneous and  cutaneous  reaction  cannot  be  identified.  Quantita- 
tive conditions,  other  unknown  factors  and  also  the  immediate 
absorption  and  diffusion  of  subcutaneous  tuberculin  in  the  body 
may  play  a  part. 

It  is  also  striking  that  the  tuberculin  reaction  is  accompanied 
by  fever,  while  a  fall  of  temperature  is  characteristic  of  hyper- 
susceptibility. But  this  collapse  temperature  is  not  uniformly 
regular  in  its  appearance.  Friedberger  and  Mita  succeeded  in 
proving  that,  also  in  ordinary  protein  anaphylaxis,  guinea-pigs 
react  with  fever  to   very   small   doses   on    the   second    injection. 


22  TUBERCULIN   IN   DIAGNOSIS    AND    TREATMENT 

And   Bauer   showed   that   the   guinea-pig   infected   with   tubercle 

bacilli  does  not  always  react  with  fever,  but  with  some  variation  of 

temperature,  sometimes  above,  sometimes  below  the  normal ;  here, 

too,  the  small  doses  caused  fever. 

_.     .        r  _  If    we    consider    that    we    are    dealing    in 

Cham  of  Events      ,  ^  ,  .     .       .  ,         ,        .     .    ,     .■ 

human  tuberculosis  with  a  chronic  infective 

m  disease,  with  frequent  relapses  and  exacer- 

Tuberculin  Action,  bations,  the  following  chain  of  events  in  a 
tuberculin  injection  given  to  a  tubercular  patient  seems  plausible. 
By  the  tubercular  infection  there  arises  a  surcharge  of  bacterial 
protein  from  the  tubercle  bacilli ;  this  incites  the  body,  first 
locally  and  then  in  general,  to  the  formation  of  digestive  ferments 
and  leads  to  the  production  in  the  blood  of  the  patient  of 
tubercular  "  anaphylatoxin."  Now,  with  the  tuberculin  injec- 
tion new  foreign  protein  is  introduced;  as  in  ordinary  protein 
anaphylaxis,  this  is  decomposed  by  the  anaphylatoxin  and  toxic 
antibodies  are  formed  which  have  a  harmful  action  on  the 
cellular  protoplasm,  causing  it  to  degenerate  and  soften.  From 
this  there  result  disturbances  due  to  anaphylaxis  or  hyper- 
susceptibility,  as  the  expression  of  the  tuberculin  reaction.  But 
while  in  ordinary  protein  anaphylaxis  a  fall  of  temperature  is 
characteristic,  owing  to  the  large  quantities  of  protein,  in  tuber- 
culosis the  reaction  due  to  hypersusceptibility  takes  the  form  of 
tuberculin  fever  on  account  of  the  extremely  small  doses,- 
thousands  of  times  below  the  lethal  amount.  This  event  is 
accompanied  on  the  one  hand  by  a  destruction  of  the  bacteria, 
on  the  other  by  a  neutralization  of  the  toxins  which  circulate  in 
the  organism  of  the  tubercular  patient  and  thus  result  the  im- 
provement and  sense  of  general  well-being  that  we,  in  conjunc- 
tion with  F.  Kraus,  Saathof,  Hager,  Longard,  and  others,  have 
so  often  observed  to  follow  severe  tuberculin  reactions. 


5.— THE  THEORY  OF  NON-SPECIFIC  ACTION. 

-ru      ail.  A    certain    number    of   authors   ascribe    the 

The  Albumose  ,  .  . 

tuberculin    reaction    to   the   action    of    non- 

'"  specific    substances    which    pass    into    the 

preparation  from  the  culture  medium  during  the  manufacture  of 
the  tuberculin.  This  brings  us  back  to  the  old  albumose  theory 
advanced  by  Kiihne  [30],  Matthes  [31],  and  Krehl  [32],  accord- 
ing to  which  tuberculin  action  is  explained  in  the  following  way  : 
The  tuberculin,  which  contains  abundant  albumoses,  is,  after 
injection,   attracted  to  the  albumoses  in   the  diseased  areas  and 


THEORETICAL    PART  23 

produces,  wherever  it  meets  with  other  albumoses,  i.e.,  in  the 
tubercular  focus,  a  local  reaction ;  it  also  flushes  albumoses 
out  of  these  areas,  causing  a  general  febrile  reaction.  This 
explanation  bears  a  close  analogy  to  Wassermann's  theory,  but 
it  takes  no  account  of  the  differences  between  the  albumoses 
and  tuberculin  already  recognized  by  Zupnik  [33]  and  Matthes 
and  Krehl  [32],  differences  which  prove  that  tuberculin  must 
contain  something  specific.  For  instance,  in  order  to  obtain  a 
toxic  albumose  effect,  much  greater  doses  are  necessary  than  are 
employed  in  the  diagnostic  use  of  tuberculin.  This  Krehl, 
Matthes,  Beraneck,  Freymuth,  and  Landmann  have  pointed  out. 
A  tubercular  animal  which  reacts  with  fever  to  1  mg.  old  tuber- 
culin, and  to  10  mg.  peptone,  receives  in  the  tuberculin  injection 
1/10  mg.  of  peptone,  the  hundredth  part  of  the  amount  of  pep- 
tone necessary  to  promote  a  peptone  reaction.  The  final  blow  to 
the  albumose  theory  is  given  by  the  fact  that  with  albumose-free 
tuberculin  prompt  specific  results  can  be  obtained. 

In  reviewing  the  various  explanations  of 
Conclusions.  tjie  tuberculin  reaction,  Wassermann's 
theory  still  seems  to  have  a  satisfactory  theoretical  foundation. 
In  strict  contrast  to  the  albumose  theory,  it  asserts  the  specificity 
of  the  tuberculin  reaction  and  of  tuberculin  itself,  which  has, 
moreover,  been  demonstrated  by  so  many  experiments  that  it 
must  be  looked  upon  as  an  axiom. 

A  further  point  is  that  specific  hypersusceptibility  has  an 
application  in  harmony  with  the  experience  of  tuberculin  treat- 
ment. The  constant  and  uniform  factor  in  all  tubercular  subjects 
is  the  presence  of  antibodies,  the  variable  factor  through  all  shades 
of  difference  the  hypersusceptibility.  The  latter  is  only  the 
factor  which  determines  the  quantitative  reactivity  of  the 
organism,  while  the  qualitative  factor  is  the  presence  of  anti- 
bodies in  the  tubercular  individual,  be  these  designated  anti- 
tuberculin,  complement-fixing  reactionary  bodies,  albuminolytic 
or  bacteriolytic  amboceptors,  or  sessile  receptors.  But  at  any 
rate  the  degeneration  of  the  tissues  themselves  is  a  partial  cause 
of  the  hypersusceptibility  shown  by  the  tubercular  organism. 

As  far,  then,  as  our  present  knowledge  goes,  the  explanation 
of  the  specificity  of  the  tuberculin  reaction  is  essentially  associated 
with  the  relations  between  the  preparation  of  tubercle  bacilli 
injected  and  the  tubercular  body  or  tissues  saturated  with  anti- 
bodies. And  these  relations  ultimately  bring  us  back  again  to 
the  phenomenon  of  hvpersusceptibility,  the  laws  of  which  are 
not  yet  fully  defined. 


24  TUBERCULIN   IN    DIAGNOSIS    AND    TREATMENT 

B.-  The  Curative  Factors  of  Tuberculin 

Action. 


1.—TOX-I  MM  UNITY. 

The  disappearance  of  reaction  to  tuberculin 
""  _  was  originally  interpreted  by  R.   Koch  as 

Subjective  a    sjgn    Qf    ^e    compiete    healing    of    the 

Symptoms  ;  tubercular  tissue.  To-day  we  know  that 
this  is  not  the  case,  and  that  tolerance  of  tuberculin  is  to  be 
considered  an  immunization  against  a  bacterial  toxin,  of  which 
Koch  founded  the  first  example.  The  theory  of  antitoxins  will 
be  discussed  later;  here  we  shall  consider  immunization  against 
tuberculin  purely  from  a  clinical  standpoint.  The  systematic 
production  of  toxin  tolerance  and  finally  tox-immunity  must 
offer  advantages  to  the  organism  in  its  fight  against  the  disease, 
as  many  of  the  general  phenomena  of  tuberculosis  are  to  be 
attributed  to  the  absorption  of  the  toxic  substances  from  the 
tubercle  bacilli.  Now  it  is  most  striking  how  these  subjective 
disorders  or  general  toxic  symptoms  (such  as  headache,  palpita- 
tion, pains  in  the  chest,  discomfort,  restless  nights,  nervous 
irritabilitv,  loss  of  appetite  and  general  weakness)  very  often 
quickly  disappear  under  tuberculin  treatment  and  are  replaced  by 
a  permanent  state  of  good  health.  It  is  also  certainly  advisable 
to  immunize  the  patient  against  those  quantities  of  toxin  which  he 
mav  often  suddenly  produce  by  unusual  exertion  (auto-tuberculin"). 

In  this  connection  the  observations  of  Hollos  and 

Of  Dysmenorrhqea    Eisenstein,    lately    confirmed    by    Macht,    deserve 

and  notice.     They  state  that  dysmenorrhea  and  amenor- 

Amenorrhfpa  •        rrioea  in  manifest  and  latent  tuberculosis  regularly 

'        disappear  in  many  cases  under  tuberculin  treatment. 

According  to  this,  tubercular  intoxication  seems  to  play  an  important  part 

in  the  etiology  of  menstrual  complaints ;  we  can  confirm  both  this  conclusion 

and  the  favourable  result  of  tuberculin  treatment. 

^     *  r\u-     j.-         Also    the    objective    symptoms    of    similar 
and  of  Objective        .    .      ,       ,    J  .   ,  ,  .   , 

_  origin    (such   as   fever,    night   sweats,    hierh 

Symptoms.  1         ♦  i        i  *       ,1  1      I 

7     r  pulse-rate,    many  pleural   troubles,    glandu- 

lar swellings,  &c.)  generally  subside  more  rapidly  under  tuber- 
culin, whereas  without  it  they  belong  to  the  more  frequent 
complications  of  the  many-sided  clinical  picture  of  the  disease. 


THEORETICAL   PART  25 

In  some  sanatoria  the  slight  uncomplicated  cases  are  not  submitted  to 
tuberculin  treatment,  but  only  the  severe  cases,  in  which  the  hygienic- 
dietetic  method  alone  does  not  guarantee  the  highest  possible  degree  of 
success.  In  such  institutions  it  is  a  fact,  evident  not  only  to  the  doctors, 
but  also  to  the  patients  themselves,  that  of  those  treated  with  tuberculin — all 
cases  of  open  tuberculosis— it  is  seldom  that  a  patient  is  confined  to  bed 
from  any  indisposition,  while  of  the  others,  not  treated  with  tuberculin,  a 
certain  percentage  is  regularly  bed-ridden. 

It  has  lately  been  asserted  in  many  quar- 
a  ue  °  ters,   on  purely  theoretical  grounds  and  in 

Tox-i  mm  unity.  SUpport  of  individual  theories,  that  tox- 
immunity  may  not  be  to  the  advantage  of  the  tubercular  patient. 
We  will  mention,  therefore,  the  experiments  of  Pickert  [34],  who 
draws  attention  to  the  fact,  well  known  to  all  experienced 
tuberculin  therapists,  that  patients  whose  disease  takes  a  con- 
spicuously favourable  course  possess  a  raised  natural  resistance 
?o  tuberculin,  which  speaks  for  a  high  resistance  of  the  organism 
to  the  disease.  This  is  reminiscent  of  the  fact  that  we  [35] 
discovered  many  years  ago  that  a  large  percentage  of  slight  cases 
of  favourable  tendency  to  heal,  which  were  submitted  to  the 
hygienic-dietetic  method  alone,  showed  at  the  conclusion  of 
treatment  high  tolerance  of  tuberculin,  while,  on  admission,  they 
were  highly  sensitive  to  small  doses  of  tuberculin.  From  these 
results  we  can  at  once  draw  the  conclusion  that  also  an  artificially 
acquired  tolerance  of  tuberculin  cannot  be  disadvantageous,  but 
that  we  are  undoubtedly  on  the  right  road  in  our  therapeutic 
endeavours.  It  is  our  experience  that  just  those  patients  who 
tolerate  tuberculin  well,  i.e.,  in  whom  it  is  easy  to  produce  tox- 
immunity,  progress  favourably.  The  tuberculin  tolerance  is 
evidently  advantageous ;  it  is  a  sign  that  the  diseased  organism 
— of  its  own  power,  or  aided  by  specific  treatment,  as  the  case  may 
be — is  repelling  the  toxic  action  of  the  tubercle  bacilli,  that  it  has 
acquired  a  relative  tox-immunity.  Our  view,  which  has  received 
confirmation  vear  by  year,  is  shared  by  many  competent  authori- 
ties ;  we  will  onlv  mention  Sahli  and  Much  of  the  many  authors 
who  attempt  to  produce  tox-immunity  in  their  patients. 

_         ._  .       With   increasing   tox-immunity,    the   condi- 

Two  Forms  of  .    .  °.  '  ,. 

tion    01    insensitiveness    to    tuberculin    can 

Insensitiveness  to    occyr_      We    distinguish    two    forms,    also 

Tuberculin.  recognized    as    such    by    Hamburger    and 

Monti:    (1)   A  forced  incapacity  to  react;  (2)  a  true   immunity. 

As  the  cause  of  the  former — the  insensitiveness  of  individuals 

treated    for    a     long    time    with     tuberculin — Wassermann     [5] 

described    the    anti-tuberculin    circulating    in   the    blood.     These 

amboceptors  intercept  the  tuberculin,  neutralize  it,  and  prevent  the 


26  TUBERCULIN    IN    DIAGNOSIS    AND   TREATMENT 

focal  reaction,  for  which  reason  their  occurrence  in  the  blood  is 
to  be  avoided.  Therefore  he  claims  that  capacity  for  reaction 
should  be  maintained  in  tuberculin  treatment.  In  spite  of  our 
complete  acceptance  of  Wassermann's  theory  in  itself,  we  cannot 
accept  this  explanation  for  reasons  expressed  by  F.  Meyer 
[2]  :  he  was  able  to  show  that  sera  without  complement- 
fixing  antibodies  could  neutralize  tuberculin  in  vitro;  Citron 
proved  that  patients  without  antibodies  may  be  insensitive  to 
tuberculin  ;  Weil  and  Strauss  proved  that  susceptibility  to  tuber- 
culin is  independent  of  the  content  of  complement-fixing  anti- 
bodies in  the  serum;  also  according  to  Kretz's  phenomenon, 
already  mentioned,  a  fresh  production  of  antibodies  can  occur  in 
the  focus  in  spite  of  apparent  neutralization.  It  is,  in  addition, 
unintelligible  that  while  the  anti-tuberculin  displays  a  neutralizing 
action  in  the  serum,  in  the  focus  it  is  productive  of  reactions ; 
according  to  Ruppel,  the  combinable  amboceptors  appearing  after 
tuberculin  injection  may  in  animal  experiment  even  exert  a  healing 
influence.  Lastly  there  is  the  most  important  argument  from  a 
clinical  point  of  view,  and  one  we  can  ourselves  confirm ;  it  is  just 
in  patients  with  high  antibody  content  and  excellent  general  con- 
dition that  unmistakable  focal  reactions  can  be  observed  after 
tuberculin  injections. 

Friedberger  [28]  and  we  ourselves,  in  antithesis  to  Wasser- 
mann,  hold  that  the  insensitiveness  to  tuberculin  is  a  healing 
process  caused  by  the  curative  action  of  the  previously  formed 
antibodies.  At  the  commencement  of  treatment,  these  are  but 
scanty,  and  therefore  set  free  anaphylatoxin,  evident  in  the  form 
of  hypersusceptibility ;  but  later  in  a  successful  course  of  tuber- 
culin they  are  increased,  split  up  the  tuberculin,  and  lead  to 
insensitiveness. 

0  ,  Now  as  an  argument  against  the  advisabilitv 

Roemers  .  .     .     &  .  P  ,  , J 

01   producing   immunity  to   tuberculin,    the 

"P  "  '   work  of  Roemer  [36]  has  been  quoted,  who 

ot  Animals.  showed    that    animals    hypersusceptible    to 

tuberculosis  may  be  immune  to  a  fresh  infection.  Therefore  it  is 
argued  that  it  is  a  mistake  to  render  patients  insensitive  to  tuber- 
culin, and  that,  on  the  contrary,  an  effort  should  be  made  to 
increase  their  hypersusceptibility  to  tuberculin  in  order  to  protect 
them  against  re-infection.  But  "  hypersusceptible  to  tubercu- 
losis "  is  by  no  means  identical  with  "  hypersusceptible  to 
tuberculin."  Also,  according  to  our  experience  extending  ever 
many  years,  the  occurrence  of  hypersusceptibility  in  the  course 
of  tuberculin  treatment  has  never  been  of  advantage  to  the  patient 
in  question,  and  this  is  the  view  of  other  experienced  tuberculin 


THEORETICAL    PART  2 7 

therapists.     On  the  contrary,  we  can  point  to  a  whole  series  of 

cases  of  open  pulmonary  tuberculosis  clinically  healed  with  large 

doses  of  tuberculin  who  after  many  years  have  remained  cured, 

both  as  regards  physical  signs  and  working  capacity,  and  have 

retained  a  relatively  high  tuberculin  immunity — permanent  cures 

of  open  tuberculosis  without  hypersusceptibility. 

Opinions  of  the  nature  of  hypersusceptibility 
Conclusions.         are  not  yet  fully  cjear  .   on  this  account  we 

shall  not  attempt  to  explain  the  action  of  tuberculin  on  its  basis 
nor  draw  conclusions  from  it  with  regard  to  the  therapeutic 
employment  of  tuberculin.  Only  this  much  will  be  said  :  it  does 
not  seem  to  us  admissible  to  quote  the  hypersusceptibility  of  initial 
cases  of  favourable  prognosis  as  an  argument  for  the  maintenance 
or  increase  of  the  hypersusceptibility  in  tuberculin  treatment. 
The  favourable  prognosis  of  such  initial  cases  does  not  depend 
on  the  hypersusceptibility  in  itself,  but  on  the  smallness  of  the 
focus  of  disease.  From  a  small  focus  there  proceed  only  small 
quantities  of  antigen  for  absorption,  so  that  the  tubercular 
organism  remains  "  hypersusceptible  "  for  some  time;  this  the 
more,  the  fresher  the  process  of  the  disease.  Also,  although  it 
is  very  generally  done,  it  is  certainly  incorrect  to  apply  the  terms 
"high  susceptibility  to  toxin"  and  "cumulative  surcharge  of 
toxin  "  without  differentiation;  these  biological  reactions  are  no 
more  identical  than  the  insensitiveness  to  tuberculin  due  to  satura- 
tion of  the  antibodies  or  absence  of  power  to  react,  and  the 
immunity  to  tuberculin  as  a  sign  of  true  antitoxic  immunity  to 
the  toxin  of  tubercle  bacilli. 

2.— THE  FOCAL  REACTION. 

.         .  The    second    specific    factor    in    tuberculin 

.  action  is  the  local  hyperasmia,  most  clearly 

yperaemia.  geen  jn  reacting-  lupus  tissues.     The  inflam- 

matory hyperemia  and  the  increased  flow  of  serum  form  the 
anatomical  basis  for  the  action  in  the  diseased  tissue.  The  same 
hyperemia  is  here  at  work  as  a  healing  factor  whose  importance 
in  bacterial  infections  has  been  specially  pointed  out  by  Buchner, 
and  whose  practical  application  for  almost  every  kind  of  inflam- 
mation in  the  most  varied  diseases  Bier  has  described  as  "  the 
most  general  and  extensive  healing  method  extant."  The 
extremely  favourable  results  in  the  tuberculin  treatment  of  tubercle 
of  the  iris  are  a  strong  witness  for  the  therapeutic  significance  of 
hyperasmia  produced  by  tuberculin  ;  it  is  just  in  the  highly  vas- 
cular tissue  of  the   iris   that  a   large  degree   of   hyperemia   and 


28  TUBERCULIN   IN    DIAGNOSIS    AND   TREATMENT 

copious  saturation  with  serum  can  be  produced  by  the  local 
reaction.  And  on  the  other  hand  histological  experiments  in 
lupus  have  shown  that  local  reactions  do  not  occur  when  the 
tubercular  foci  are  excluded  from  the  circulation  by  reason  of 
fibrotic  changes.  Neither  in  such  places  nor  in  their  neighbour- 
hood does  the  staining  of  serial  sections  reveal  the  presence  of 
vessels.  The  tuberculin  is  deprived  of  the  possibility  of  reaching 
the  foci  (Klingmiiller  [37]). 

The  action  of  hyperemia  and  inflammation 
is  a  double  one  :  on  the  one  hand  absorp- 
the  Hyperaemia.  i\on^  on  the  other  demarcation,  softening, 
necrosis,  and  extrusion.  Virchow  has  justly  demanded  a  more 
precise  use  of  the  term  "  tubercular  tissue,"  a  differentiation 
between  the  tubercle,  the  tubercular  ulcer  destined  to  break  down, 
the  true  tubercular  tissue,  and  the  purely  inflammatory  changes 
of  the  tissues  adjoining  the  tubercle,  in  which  latter  tuberculin 
displays  its  action.  Thus  tuberculin  action  must  be  described 
as  follows  :  In  the  first  place,  general  infiltration  of  the  diseased 
tissue  with  blood  and  blood  cells;  then  with  decreasing  hyper- 
emia, washing  out  of  the  inflammatory  elements  into  the  blood 
and  lymph  channels,  and  by  repetition  of  this,  gradual  complete 
absorption  ;  finally,  in  all  situations  where  the  tubercular  changes 
in  the  tissues  are  so  far  advanced  that  absorption  is  no  longer 
possible,  softening  and  disintegration. 

3.— THE  ANTIBODIES  AS  CURATIVE  FACTORS. 

(a)  Antitoxins. 

Lowenstein    ficfl    and    Pickert    [~i81     have 
Lowenstem    and  ,  ,  ,  ..       ,,    .  .  im- 

proved beyond  question  that  true  antitoxins 

Pickert.  occur    in    the    blood    of    tuberculin-treated 

patients.  The  capacity  for  antitoxin  formation  is  not  developed 
to  the  same  extent  in  all  tubercular  subjects ;  where  the  disease 
has  taken  a  fibrous  character,  antitoxin  is  formed  most  readily. 
To  obtain  immunity,  comparatively  large  quantities  of  antigen 
are  essential ;  antitoxins  are  most  easily  found  in  highly  immu- 
nized patients.  The  increased  value  of  a  serum  does  not  depend 
so  much  on  the  fact  that  the  same  quantity  of  serum  can  neutra- 
lize a  larger  quantity  of  tuberculin,  but  that  the  mutual  avidity  of 
antibodv  and  antigen  is  increased,  and  the  strength  of  the  newly 
established  combination  is  greater. 

From  the  results  of  these  researches,   Lowenstein  concludes 
that  the  antitoxins  probablv  play  an  important  part  in  the  healing 


THEORETICAL   PART  2Q 

process  of  tuberculosis,  especially  when  they  are  formed  at  an 
early  stage  in  the  disease, 

Ruppel    [38],     in    the    Hochst    tubercular 
Kuppel.  serum  (described  later),  has  made  a  prepara- 

tion on  new  principles  of  his  own  which  allows  the  exact  study 
of  the  properties  of  the  serum  of  a  specifically  treated  patient. 
In  the  serum  of  the  immunized  animals  all  known  antibodies 
occur ;  it  renders  bacilli  non-toxic,  and  displays  a  protective  and 
healing  action  on  guinea-pigs.  Ruppel,  too,  explains  the  healing 
action  by  the  content  of  antitoxins. 

(b)  Agglutinins. 

,_,,..  In    the   natural    course   of    tuberculosis,    no 

Relation  between    r  .  ,  .a  ,   ^   ■         '  , 

formation     of     specific     agglutinins     takes 
Agglutinating  Power  place_       In  the  treatment  ^  animals  with 

and  Immunity.  bacterial  cultures  for  immunization  there 
appear  in  the  blood  both  agglutinating  and  immunizing  proper- 
ties. Therefore  Koch  [39]  thought  the  assumption  justified  that 
animals  artificially  raised  to  high  agglutination  values  possess  a 
certain  degree  of  immunity  against  infection  with  tubercle  bacilli. 
And,  in  point  of  fact,  he  obtained  unquestionable  proof  of  this. 
He  inclined  to  the  belief  that  the  agglutinating  property  was  part 
and  parcel  of  the  complicated  entity  of  immunity.  The  animal 
experiments  gave  colour  to  the  view  that  the  height  of  the  agglu- 
tination value  stood  in  a  certain  relation  to  the  immunity  attained, 
and  it  became  a  question  of  reaching  the  highest  possible  agglu- 
tination values  in  man.  This  is  most  successful  when  an  extremely 
fine  emulsion  of  pulverized  tubercle  bacilli  in  physiological  saline 
solution  is  employed  for  immunization. 

Arloing  and  Courmont  had  already  succeeded,  by 

Agglutination  injections    of    attenuated  tubercle   cultures,    in    in- 

Value    in  creasing   the   agglutinating  power   in   animals;    up 

Tuberculin  t0  T  :  6°°  in  a  dog.     Koch  went  further  and  obtained 

Treatment  an    'dSS^-ut^nat^S   power   of    1  :3,5oo   in    a    donkey. 

The   highest  agglutination  values   noted   by   Koch 

with   his   method   were    1  :  200   and    1  :  300,  but  his   were   for  the  most  part 

severe  cases.     We  have  obtained  values  of    1  :i,ooo  even   with   patients   in 

Stadium  3.     The  outcome  of  these  investigations   [40]   into  the  occurrence 

and  significance  of  agglutination  during  tuberculin  treatment  can  be  stated 

as  follows  : — 

(1)  By  treatment  with  bacillary  emulsion  the  agglutinating  power  can 
almost  always  be  raised. 

(2)  The  better  the  prospect  of  improvement  or  recovery,  the  more 
rapidly  the  agglutinating  power  rises  and  the  greater  the  extent  and  dura- 
tion of  the  rise. 

(3)  The  more  unfavourable  the  outlook,  the  more  difficult  it  is  to  raise 


30  TUBERCULIN    IN   DIAGNOSIS   AND  TREATMENT 

the  agglutinating  power  at  all  and  the  more  rapidly  it  is  lost ;  persistence  of 
a  very  low  agglutination  value  denotes  in  general  progressive  disease. 

(4)  Determination  of  the  agglutinating  power,  although  of  great  value 
and  interest,  is  not  to  be  regarded  as  an  essential  factor  in  the  technique 
of  tuberculin  treatment. 

_  _,  Hence   when    Koch    writes:    "The   agglu- 

The  Proper  Place      .     t.  .,     ,      ,  ,u  ■     & 

r  .  tination    method   places   the   means    in    our 

ot  the  Agglutina-  hallcls  of  making  sure  step  by  step  whether 
tion  Method.  we  are  on  the  right  road  with  our  attempts 
at  immunization,  and  puts  an  end  at  one  blow  to  the  earlier 
uncertainty,"  the  application  is  to  immunizing  processes  in 
general,  not  to  the  treatment  of  the  individual.  For  the  agglu- 
tinating process  is  a  valuable  indication  that  by  means  of  tuber- 
culin treatment  processes  of  a  really  specific  nature  are  started  in 
the  body,  and  substances  formed  which  possess  a  specific  action 
on  the  protoplasm  of  the  tubercle  bacilli.  From  experience  with 
other  bacteria  we  know  that  the  production  of  agglutinating  sub- 
stances takes  place  regularly  in  the  process  of  immunity,  and 
hence  in  the  specific  treatment  of  tuberculosis  the  phenomenon  of 
agglutination  is  a  valuable  criterion  for  the  simultaneous  occur- 
rence of  immunizing  processes. 

This  connection  between  agglutination  and  immunity  has  by 
no  means  been  given  up,  but  as  the  agglutination  value  often 
gives  no  definite  clue  in  an  individual  case,  more  attention  has 
lately  been  paid  to  the  study  of  bacteriotropic  substances  and  those 
producing  fixation  of  complement.  The  agglutinins  are  by  no 
means  identical  with  the  immune  bodies,  least  of  all  can  the  con- 
tent of  agglutinins  in  the  serum  be  considered  as  an  indication 
of  the  actual  degree  of  immunity  attained,  but  they  indicate  the 
presence  of  specific  reactionary  processes  in  the  organism. 

Christian  and  Rosenblat  [6]  have  made  a  valuable  contribution  to  the 
importance  of  agglutination  and  the  curative  power  of  bacillary  emulsion 
in  experimental  tuberculosis  of  guinea-pigs  in  their  researches  on  the  anti- 
bodies of  tuberculosis  and  immunity  to  the  disease.  They  succeeded  in 
proving  exquisite  healing  processes  with  very  considerable  formation  of 
connective  tissue  in  guinea-pigs  during  treatment  with  bacillary  emulsion, 
at  the  same  time  showing  the  inconclusiveness  of  Jiirgen's  unsuccessful 
experiments  on  animals  and  the  deductions  which  he  drew  from  them. 

(c)  Opsonins. 

-r.      n  .  Wright's  [41]  opsonic  theory  is  a  work  of 

The  Opsonic  :  •   ,  ,  .  ,   r 

great  interest,  and  essential  for  the  proper 

eory  o  understanding     of     the     cellular     processes 

Wright  ;  attending    the    specific    therapy    of    many 


THEORETICAL   PART  31 

infectious  diseases,  above  all  of  tuberculosis;  a  work,  further, 
which  has  again  brought  Metchnikoff's  phagocytic  theory  into 
recognition.  Metchnikoff  had  already  made  the  observation  that 
many  infecting  agents  when  introduced  into  the  normal  body 
called  forth  little  or  no  phagocytosis,  while  in  artificially  immu- 
nized animals  the  process  made  itself  actively  felt.  Further 
investigation  showed  that  during  immunization,  substances  were 
formed  in  the  serum  which  stimulated  phagocytosis  (Metchni- 
koff's stimulins).  More  recent  work  confirmed  the  enormous 
significance  in  the  mechanism  of  immunity  of  the  taking  up  of 
bacteria  by  the  cells,  and  showed  that  this  happens  under  the 
influence  of  a  substance  of  the  nature  of  an  amboceptor,  called 
by  Wright  opsonin.  Wright  now  elaborated  a  method  enabling 
the  opsonic  power  of  a  serum  to  be  determined  by  a  numerical 
comparison  of  the  phagocyted  bacteria  under  constant  experi- 
mental conditions.  The  ratio  of  the  opsonic  content  of  the  serum 
of  a  patient  to  that  of  a  healthy  individual  Wright  calls  the 
opsonic  index,  and  this  gives  an  objective  standard  of  the  content 
of  the  blood  in  antibacterial  substances  and  a  guide  for  thera- 
peutic measures. 

Wright   constantly   found   a  period   of  intoxication 

US    Deductions       varying  with  the  amount  of  vaccine  administered, 

and    Practical  during  which  the  antibacterial  power  of  the  blood 

«        •-       ,.  was  reduced.     On  this  negative  phase   followed  a 

""  positive    one,     with    increase    of    the    antibacterial 

power,   lasting   in   the  case   of   tuberculosis   for   about    a   month.      On   this 

account  he  holds  frequent  injections  of  tuberculin  to  be  useless,  increasing 

the  negative  but  not  the  positive   phase.     The  proportion   of   antibacterial 

substances  in  the  blood  is  also  not  proportional  to  the  quantity  of  tuberculin 

injected.     Wright  accordingly  worked  with  minute  quantities  of  tuberculin, 

commencing  with  a  dose  of  o'oooi  c.mm.    (mostly  new  tuberculin,  less  with 

old),  under  constant  control  of  the  opsonic  index  during  the  negative  phase. 

If  the  length  of  this  increases  the  dose  is  too  large ;   if  it  decreases  it  is 

evidence  of  the  correctness  of  the  dose.     Wright  has  employed  his  method 

extensively    in    localized    tuberculosis,    pulmonary    excepted,    and    produced 

perfect  healing  in  severe  cases  of  lupus,  deep  tubercular  ulcers  of  the  skin, 

large  glandular  swellings  in  the  neck,  as  well  as  in  cases  of  tuberculosis  of 

bone,  joints,  and  urogenital  system.     In  mixed  infections  he  immunizes  both 

against  the  tubercle  bacilli  and  the  other  infecting  agent  present. 

.  ^  Wright's    method    of    dosage    agrees    with 

Larger  Doses         ,      b  ■    .  •    ,  .    &+ ,     &+  ,         .. 

the  requirements  of  certain  other  tuberculin 

ecessary.  therapists    (such    as    Nournay    and    Jessen) 

that   only   the   smallest   quantity   of   tuberculin    should   be    used, 

even  in  the  treatment  of  pulmonary  tuberculosis.     According  to 

our  interpretation   of  the  theory  of  tuberculin   action,   and  after 


32  TUBERCULIN   IN   DIAGNOSIS    AND   TREATMENT 

many  years'  practical  experience,  the  use  of  larger  doses  of 
tuberculin,  though  very  gradually  and  cautiously  increased, 
cannot  be  dispensed  with.  Many  reasons  can  be  given  for  this 
standpoint.  The  correctness  of  our  view  is  confirmed  by  the 
works  of  Turban  and  Baer  [42]  on  the  practical  significance  of 
the  opsonic  index. 

They    are    of     opinion    that     the     observation     of 

Glinical  Wright's   rule — to   make   the   dosage   dependent   on 

Observation    more    the  phase — restricts  the  physician  too  much  to  the 

i™^^*~+ -..-,+  use   or  trie   smallest   doses,   which,    apart   from  the 

imporianT.  .  ,  ,.    .        _.  , 

1  treatment   or    severe   cases,    have   little   effect,   and 

more  easily  produce  hypersusceptibility  than  the  larger  ones.  At  any  rate, 
the  results  obtained  by  Turban  with  larger  doses  of  tuberculin  without 
opsonic  control  were  better,  in  spite  of  the  fact  that  Wright's  rule  must 
certainly  often  have  been  broken.  Turban  and  Baer  take  Up  our  stand- 
point that  in  tuberculin  treatment  clinical  observation  (temperature,  weight, 
subjective  and  objective  condition,  &c.)  is  more  important  than  the  deter- 
mination of  the  opsonic  index,  "  the  marked  fluctuations  of  which  make  the 
physician  over-anxious  and  the  patient  hypersusceptible." 

.  .     ..    ..  r  ..       In   our   opinion    the   present   extent   of  our 

Limitations  of  the    ,  ,    ,  r    1  ,•         ,  ,    , 

knowledge  of  the  complicated  behaviour  of 

Va  ue  of  the         .,  •     ,  .   u        ,     •  , 

the    opsonic    index    in     tuberculosis,     and 

Opsonic  Index.  especially  in  the  form  of  most  practical 
importance — pulmonary — does  not  speak  for  the  value  and  utility 
of  Wright's  method.  It  has  also  been  pointed  out,  especially  by 
Lohlein  (on  the  basis  of  Metchnikoff' s  observation  in  guinea- 
pigs  with  regard  to  the  behaviour  of  the  leucocytes  to  anthrax 
bacilli),  that  pathogenic  organisms  after  penetrating  into  the  body 
often  acquire  a  greatly  increased  power  of  resistance  to  phago- 
cytosis ;  and  Lowenstein  has  made  the  observation  that  tubercle 
bacilli  present  in  the  body  offer  an  incomparably  greater  resistance 
to  phagocytosis  than  do  those  in  culture.  All  observers,  however, 
including  Wright  himself,  agree  it  is  just  in  cases  of  phthisis 
that  the  fluctuation  of  the  opsonic  content  is  exceedingly  large ; 
so  large,  in  fact,  that  short  walks,  even  simple  bodily  exercises, 
give  rise  to  great  variations  of  the  index  by  introducing  toxins 
into  the  circulation.  This  considerably  limits  the  value  of  the 
opsonic  determination.  In  addition,  there  is  a  point  of  great 
importance,  which  on  the  basis  of  our  own  observations  we  must 
hold  as  crucial  :  the  complicated  and  difficult  technique  of  the 
method,  with  its  sources  of  error  both  numerous  and  incalculable. 

How  much  the  estimation  of  the  opsonic  index  depends  on  the  subjective 
judgment  is  evident  from  a  communication  made  by  F.  v.  Miiller  at  the  Con- 
gress of  Tuberculosis  Specialists  at  Munich  in  1908,  reported  as  follows  in 
English  literature  :    the   same  serum   was   given   to  eleven   laboratories   for 


THEORETICAL    PART  33 

examination,  and  in  almost  every  laboratory  a  different  opsonic  index  was 
found ;  some  gave  it  as  positive,  some  as  negative,  the  variation  being 
from  o'8  to  i'j. 

In  this  way  the  opsonic  index  loses  its 
practical  value  for  a  large  section  of  practi- 

Significance.  tioners  who  can  and  must  take  part  in  the 
specific  treatment  of  tuberculosis.  Its  place  as  a  difficult  clinical 
method  is  in  special  institutions  with  assistants  working  at  it 
alone,  thus  losing  its  significance  in  the  treatment  of  a  widespread 
disease.  These  considerations  do  not  detract  from  the  scientific 
value  of  Wright's  teaching  nor  the  forward  step  thus  taken ;  it 
is  calculated  to  confirm  and  intensify  the  conception  held  to-day 
of  the  beneficial  effect  of  tuberculin  in  general,  and  especially  to 
justify  and  strengthen  the  modern  principle  of  a  carefully 
graduated  tuberculin  treatment.  We  are  of  the  same  opinion  as 
Neufeld  [43],  and  for  the  present  value  the  appearance  of 
opsonins  during  specific  treatment  with  tuberculin  only  in  the 
sense  "  that  we  conclude  from  their  appearance,  just  as  from 
that  of  agglutinins,  that  a  specific  reactive  process  is  certainly 
taking  place  in  the  organism  without,  however,  any  certainty  that 
the  opsonins  are  the  immunizing  substances  which  immediately 
bring  about  the  healing  process,  and  without  even  admitting 
that  the  quantity  of  these  is  a  direct  expression  of  the  degree  of 
immunity  attained." 

Even  Wright  and  his  pupils  have  given  up  the  constant 
control  of  the  opsonic  index  in  the  treatment  of  chronic  cases  of 
tuberculosis. 

(d)  Phagocytosis. 

Importance  of       Pha8ocytosis,   in   Metchnikoff's   sense,    has 

'  .  in    any   case   a    role    in   the    mechanism    of 

°       .  '        immunity    in    tuberculosis    during    specific 

MetchmkofT.  treatment,  and  we  hold  it  to  be  of  greater 
practical  importance  than  the  complicated  determination  of  the 
opsonic  index,  as  well  as  much  simpler  to  demonstrate.  But  its 
significance  is  not  nearly  sufficiently  recognized  and  explained. 

According  to  v.  Baumgarten,  phagocytosis  has  no  bacteri- 
cidal action  on  the  bacteria,  the  destruction  taking  place  in  the 
serum.  From  his  investigations  he  concludes  that  the  phagocytes 
at  most  digest  dead  organisms,  and  that  phagocytosis  disappears 
altogether  in  the  immunized  organism. 

Other  investigators,  however,  state  that  its  utility  cannot  be 
doubted,  whether  it  eliminates  the  tubercle  bacilli  from  the  circu- 
lation   and    prevents    their    increase,    or    whether,    according    to 

3 


34  TUBERCULIN    IN    DIAGNOSIS    AND   TREATMENT 

Bartel  and  Neumann,  it  brings  about  the  transport  of  the  bacilli 
into  the  lymphatic  glands  and  the  spleen,  which  are  to  be  con- 
sidered the  real  organs  of  protection  and  destruction. 

Detailed    work    on    phagocytosis    in    pul- 
Lowenstein.  monary  tuberculosis  has  chiefly  been  pub- 

lished by  Lowenstein  [44],  who  has  noted  intracellular  grouping 
of  the  bacilli  in  the  leucocytes  of  sputum,  often  with  decreased 
intensity  of  staining  and  retrogressive  metamorphosis  in  the  more 
favourable  cases,  especially  those  undergoing  treatment  with 
tuberculin.  An  interesting  addition  is  furnished  by  the  investi- 
gations of  Morland  [45],  who  noticed  the  intracellular  grouping 
in  patients  undergoing  specific  treatment  exclusively  and  almost 
regularly  in  the  positive  phase. 

We  have  confirmed  Lowenstein's  observations,  but 
Phagocyte  the    microscopic   proof    is    difficult    with   the    usual 

Stain inff  Ziehl-Neelson  or  Gabbet  staining  method  on  account 

of  the  danger  of  damage  to  the  protoplasm  of  the 
leucocytes.  The  following  precautions  are,  therefore,  advisable  :  cover- 
glass  preparations  are  made  with  a  platinum  loop  from  about  ten  different 
parts  of  the  sputum,  the  film  being  very  thin  and  care  taken  not  to  damage 
the  leucocytes.  To  this  end  Pfeiffer's  injunction  not  to  rub  the  slips  on 
each  other  must  be  observed.  The  sputum  is  examined  as  fresh  as  possible 
to  avoid  the  appearance  in  the  leucocytes  of  degenerative  changes.  The 
preparation  is  carefully  dried  and  fixed  and  then  stained  with  carbol- 
fuchsin  over  the  flame;  bubbles  must  on  no  account  be  allowed  to  rise. 

_,.      .c  r       Present  research  shows  that  the  process  of 

Significance  of         .  .      .  ...... 

.  phagocytosis    is    an    extraordinarily    wide- 

agocy  osis.  spread  one,  and  is  regularly  present  when  the 
infection  takes  a  favourable  turn  for  the  organism  (Kruse  [46]). 
Views  only  differ  as  to  whether,  as  Metchnikoff's  holds,  phago- 
cytosis is  the  causal  factor,  or  whether,  as  most  of  the  German 
workers  in  immunity  consider,  phagocytosis  only  occurs  when 
the  fate  of  the  infecting  agent  is  already  decided  by  other  bacteri- 
cidal forces.  But  even  so,  it  must  not  be  forgotten  that  "an 
extraordinarily  important  service  might  be  rendered  to  the  infected 
organism,  as  simultaneously  with  the  elimination  of  the  already 
weakened  or  killed  bacteria,  a  detoxication  of  the  bacterial  bodies, 
or  at  least  a  considerably  slackened  absorption  of  toxin,  may  take 
place,  which  in  itself  might  be  of  decisive  importance  in  the  course 
of  the  process  of  disease  "  (P.  Th.  Miiller  [47])- 

(e)  Bacteriotropins  and  Bacteriolysins. 

Bacteriotropins      in      tuberculin     treatment 

have     been     studied     by     Bohme    and     bv 

Lowenstein.     According  to  Bohme  [48],  the  serum  of  tubercular 


THEORETICAL    PART  35 

patients  not  treated  with  tuberculin  and  also  that  of  normal 
individuals  may  contain  tuberculotropins.  In  slight  cases  they 
are  found  only  in  a  relatively  small  percentage,  in  severe  cases  in 
the  majority  of  patients.  After  treatment  with  bacillary  emulsion 
these  antibodies  were  relatively  increased  in  all  the  sera  examined. 
In  confirmation  of  Bohme's  results,  Lowen- 
stein  [19]  proved  that  in  clinically  favour- 
able cases,  even  when  treated  with  old  tuberculin,  no  increase  of 
these  bodies  occurs ;  they  appear  to  be  connected  with  the  employ- 
ment of  bacillary  emulsion. 

Both  authors  agree,  however,  that  there  is  no  strict  connec- 
tion between  the  course  of  the  disease  and  the  content  of 
bacteriotropins. 

This  is  not  so  in  the  case  of  bacteriolysins.  According  to  the 
experiments  of  R.  Kraus  and  Hofer  [49]  (on  the  lines  of  the  well- 
known  researches  of  Pfeiffer)  tubercle  bacilli  in  the  organism  can 
be  destroyed  by  bacteriolysis  as  well  as  by  phagocytosis.  The 
bacteriolytic  bodies  for  tubercle  bacilli  are  produced  in  increased 
quantities  in  the  tubercular  organism  and  their  presence 
can  be  proved  in  the  serum.  This  raised  bacteriolytic  power  of 
tubercular  patients  helps  to  explain  their  immunity  to  re-infection. 
They  command  a  greater  supply  of  bacteriolysins  compared  with 
healthy  individuals  but  less  opsonins  and  bacteriotropins,  as 
Wright  has  shown.  Therefore  in  the  healthy  organism  the  chief 
role  is  played  by  phagocytosis,  while  in  the  tubercular  bacterio- 
lysis is  predominant  in  spontaneous  healing  and  in  immunizing 
processes.  We  have  no  very  definite  knowledge  of  the  bacterio- 
lytic bodies,  especially  as  the  normal  serum  of  man  and  animal 
has  a  certain  bacteriolytic  power.  We  know,  however,  that  thev 
are  present  in  increased  amount  in  tubercular  serum. 

Many  clinical  observations  point  to  the  fact  that  the  bacterio- 
lytic resources  of  the  organism  are  increased  by  specific  treatment. 
Certain  forms  of  the  so-called  reaction-fever,  increase  of  sputum, 
disintegration  of  the  tubercle  bacilli,  &c,  are  connected  with  it. 
Also  Wolff-Eisner's  and  Sahli's  explanation  of  the  tuberculin 
reaction   can  be  brought  into  line  with   it. 

(f)  Complement-fixing  Antibodies. 

Bauer  and  ^ie   aPPearance    °f    the    complement-fixing 

,_        .,     _  antibodies  already  mentioned  in  the  blood  of 

tnsrels  HJesults 
. &        .  specifically  treated  tubercular  patients  seems 

in   Children.  to  be  of  considerable  significance.       What 

Christian  and  Rosenblat  [6]   demonstrated  in  tubercular  guinea- 


36  TUBERCULIN   IN   DIAGNOSIS   AND   TREATMENT 

pigs,  Engel  and  Bauer  [50]  have  confirmed  in  tubercular  suck- 
lings and  young  children  ;  with  appropriate  tuberculin  treatment 
they  were  uniformly  successful  in  demonstrating  the  existence  of 
antibodies  producing  fixation  of  complement  in  the  serum,  not 
formed  like  the  agglutinins  in  normal  cells,  but  in  the  tubercular 
tissue.  Moreover,  Bauer  and  Engel  succeeded  in  proving  by 
quantitative  tests  that  with  the  quantity  of  tuberculin  injected 
a  corresponding  amount  of  these  antibodies  was  formed  in  the 
blood,  increasing  to  a  maximum.  It  deserves  special  notice  that 
a  considerable  quantity  of  antibodies  was  only  formed  when 
relatively  high  doses  had  been  reached. 

Bauer  and  Engel's  results  in  the  specific  treatment  of  tuber- 
culosis in  children  agree  with  those  of  Jochmann  and  Moller  [51 
and  52]  in  adults.  Thev  succeeded  in  general  in  producing  anti- 
bodies in  the  serum  of  the  patients  treated,  and  this  only  when 
he  approached  the  maximum  dose.  They  are  more  reserved  with 
regard  to  the  conclusions  to  be  drawn  from  the  phenomenon. 
They  saw  patients  clinically  completely  cured  with  increasing 
formation  of  antibodies ;  others  did  as  well  without  them  ;  others, 
again,  grew  worse  and  died  with  continual  increase  of  antibodies. 
In  spite  of  these  conflicting  results,  they  with  Koch  looked  upon 
the  occurrence  of  the  phenomenon  as  the  indication  of  the  forma- 
tion of  certain  protective  forces,  which,  in  the  cases  which  turned 
out  unfavourablv,  may  have  come  too  late  or  not  in  sufficient 
quantity. 

These  results  seem  to  prove  the  inferior  value  of  exclusively 
small  doses  of  tuberculin  as  expressly  demanded  by  Wright's 
opsonic  theory  and  by  several  authors. 

The  increase  of  antibodies  can  possibly  be  used  as  a  general 
guide  to  the  further  course  of  treatment,  so  that  the  method  of 
complement  fixation  may  eventuallv  prove  valuable  for  the  control 
and  direction  of  specific  treatment — a  prospect  which,  by  means  of 
the  continued  estimation  of  agglutinins  and  the  opsonic  index,  has 
not  yet  been  fulfilled.  It  would  also  be  of  practical  importance, 
as  the  technique  of  fixation  of  complement  is  one  which  can  be 
carried  out  without  difficulty  in  every  institution  and  hospital. 


II. -The   Specific   Diagnosis  of 
Tuberculosis. 


A. — General   Section. 

For  the  specific  diagnosis  of  tuberculosis  the  following  tuber- 
culin tests  come  into  consideration  :  (i)  The  cutaneous,  (2)  the 
conjunctival,  (3)  the  subcutaneous. 

~.            .  All   tuberculin  tests  have  this  in  common, 

Diagnosis  ' 

_   ,           ,.  that  they  make  a  diagnosis  possible  by  the 

by  Tuberculin  ,  .   ,          v             .■            -f, 

7  appearance  01   tuberculin   reactions.      I  hese 

Reaction.  are    to    j-^    ta^en    as    reactions    of    hyper- 

susceptibility  and  analogous  to  immunity  reactions,  both 
cellular  and  humoral.  On  the  other  hand  they  are  dis- 
tinguished from  one  another  by  the  fact  that  in  the  case 
of  the  cutaneous  and  conjunctival  tests  where  the  tuberculin 
is  introduced  into  the  tissue  spaces  of  the  skin  or  the  mucous 
membrane,  the  reaction  remains  localized  at  the  point  where 
the  tuberculin  has  taken  effect ;  whereas  subcutaneous  injec- 
tion brings  the  tuberculin  into  the  circulation,  and,  in  addition  to 
general  signs  of  reaction,  sets  free  processes  tending  to  hyper- 
emia and  exudation  in  the  tubercular  focus. 

With  regard  to  the  specific  nature  of  the  tuberculin  reactions 
it  remains  to  be  noted  that  they  cannot  appear  quite  regularly 
and  equally  clearly  in  each  and  every  patient.  And  this  on 
account  of  the  dependence  of  every  kind  of  biological  reaction  on 
the  susceptibility  of  the  organism,  on  its  powers  of  reaction  and 
reactionary  products,  and  on  the  irritant  power  of  the  antigen  in 
question.  The  conditions  for  tuberculin  reactions  are  rendered 
specially  difficult  and  complicated  because  almost  every  human 
being  at  some  time  or  other  harbours  tubercle  bacilli.  But  tuber- 
cular infection  and  tubercular  disease  are  by  no  means  identical, 
and  only  the  latter  interests  the  diagnostician.  We  must  there- 
fore be  prepared  for  small  but  very  essential  deviations  in  indi- 
vidual tuberculin  reactions. 


38  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

1.— THE  CUTANEOUS  TUBERCULIN  TESTS. 
(a)  Cutaneous  Test  according  to  v.  Pirquet. 

The  technique  of  the  cutaneous  tuberculin 
Technique.  inoculation-  is  very  simple,   and  in  general 

follows  that  of  vaccination ;  it  should,  nevertheless,  to  exclude 
failure,  accurately  follow  the  directions  of  v.  Pirquet.  For  imple- 
ment a  platino-iridium  lancet  will  serve,  or  better,  the  specially 
constructed  scarifier  of  v.  Pirquet. 


„  .  The  tuberculin  preparation  used  is  Koch's 

Preparation  .  ,     ,   ,  r     r 

r  old     tuberculin,     and     this     may     be     con- 

veniently  stored  in  a  bottle  with  ground-in 

pipette  stopper,  also  suggested  by  v.  Pirquet. 

We  have  lately  made  an  extensive  series  of  experiments  with  Koch's 
tuberculin  free  from  albumose  side  by  side  with  old  tuberculin,  but  cannot 
recommend  the  former,  because  when  used  cutaneously  it  offers  no  advan- 
tages from  the  point  of  view  of  diagnosis,  is  rather  less  reliable,  and,  more- 
over, is  considerably  dearer. 

At  first  v.  Pirquet  [$3~\  employed  a  25  per  cent,  dilution  with 
\  per  cent,  carbolic  acid,  but  quite  recently  has  given  the  preference 
to  undiluted  tuberculin.  If  the  latter  is  used  the  test  need  only  be 
employed  a  single  time,  whereas  a  negative  reaction  with  the 
25  per  cent,  dilution  renders  the  repetition  with  undiluted  tuber- 
culin advisable.  The  test  is  therefore  simplified  by  the  immediate 
use  of  the  stronger  preparation,  but  there  is  some  justification 
for  the  objection  that  the  reaction,  which  is  alreadv  very  delicate, 
becomes  thus  still  more  so,  and  is,  in  fact,  too  easilv  provoked. 
We  have  some  observations  of  our  own  in  which  the  cutaneous 
inoculation  with  undiluted  tuberculin  gave  well-marked  positive 
result  in  cases  of  clinically  doubtful  diagnosis,  whilst  the 
simultaneous  test  with  25  per  cent,  dilution  as  well  as  the 
fourfold  repetition  of  the  conjunctival  test  were  negative,  and 
this  was  finally  confirmed  by  a  negative  result  with  the  sub- 
cutaneous method. 

On  the  other  hand  we  have  also  noticed  cases  in  which  the 
first  cutaneous  inoculation  with  undiluted  tuberculin  was  negative 
and  only  the  second  positive. 

We  recommend  for  adults  the  use  of  the  undiluted  tuberculin, 
and  leave  undecided  whether  for  children  the  25  per  cent,  dilution 
or  the  undiluted  preparation  deserves  the  preference. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS 


39 


For  purposes  of  comparison  one  scarification  can  be  treated 
with  one  and  one  with  the  other.  In  doubtful  cases,  in  which  the 
result  is  negative  with  25  per  cent.,  and  positive  with  undiluted 
tuberculin,  the  subcutaneous  method  must  decide. 


The  best  site  for  inoculation  is  the  inner  side  of  the 
forearm,  because  of  its  delicate  and  less  hairy  skin  and  the  ease 
of  observation. 

The    skin    is    rubbed    with    ether,    two    drops    of    tuberculin 


placed  on  it  at  a  distance  of  about  4  in.  apart,  and  circular 
scarifications  made  with  the  needle,  first  midway  between  the 
two  drops  and  then   in  the  middle  of  each. 

It    is    sufficient    to    open    only    the    most    superficial    lymph 


40  TUBERCULIN   IN    DIAGNOSIS    AND   TREATMENT 

channels  by  scraping  off  the  layers  of  epidermis;  any  considerable 
oozing  of  blood  is  as  much  to  be  avoided  as  in  vaccination.  The 
process  is  made  bloodless  by  seizing  the  forearm  with  the  left 
hand,  stretching  the  skin  and  making  with  the  needle,  held 
vertically  between  the  fingers  of  the  right  hand,  .a  rotatory 
scratching  movement.  The  more  delicate  the  skin  the  less 
pressure  should  be  made  with  the  chisel-like  platinum  end  of 
the  instrument.  On  the  other  hand,  it  is,  of  course,  necessary 
to  make  a  lesion  ;  and  the  inoculation  must  be  held  to  have  been 
too  superficial  when,  on  inspection  later,  no  kind  of  scab  is  to 
be  seen. 

The  platinum  point  must  be  sterilized  before  use  each 
time  by  heating  it  red-hot,  to  avoid  the  possibility  of  carrying 
over  infections  from  case  to  case ;  and  after  every  inoculation 
it  must  be  carefully  cleaned  of  every  trace  of  adherent  tuberculin, 
which  might  otherwise  be  inoculated  into  the  control  site  of  the 
next  patient  and  spoil  the  comparison  of  the  control  inoculation 
with  the  others ;  or  two  needles  may  be  kept,  one  for  the  control 
site,   the  other  for  the  scarifications  in   the  drops  of  tuberculin. 

After  the  inoculation  the  tuberculin  is  allowed  to  soak  into 

the  tissue  spaces  for  some  minutes,  or  a  piece  of  cotton-wool  is 

applied,    small    enough    to    be    quite    soaked    by    the    drop.     No 

dressing  is  necessary. 

.  x.  ,        The    most    favourable    time    for    a    single 

Inspection  of  .  .  r  A.     ,  .  x.       .  ?  , 

1  revision  ol  the  inoculation  is  after  a  period 

Result 

of    forty-eight    hours.      If   daily    inspection 

is  possible  the  result  should  be  controlled  after  twenty-four  and 
forty-eight  hours,  and  in  order  not  to  overlook  the  possible 
occurrence  of  a  late  reaction,  again  after  three,  four,  and  eight 
days. 

In  interpreting  the  reaction  a  distinction  must  be  made 
between  :  — 

(i)  The  traumatic  reaction  arising  from  the  scarification  itself. 

(2)  The  inoculation  with  negative  reaction. 

(3)  The  positive  cutaneous  reaction. 

As  this  is  in  practice  not  always  quite  easy  and  may  lead 
to  errors  of  diagnosis,  the  differences  between  them  will  now 
be  discussed  in  detail,  based  on  800  observations  of  our  own 
in  adults  and  on  v.  Pirquet's  much  larger  clinical  material  in 
children. 

The  traumatic  reaction  arises  within  a  few 
Types  of  Reaction  ;    minutes    at    the    site    both    of    control    and 
the  Traumatic.       inoculation,  and  in  the  same  way.     It  con- 
sists  as  a   rule  of  a   small   raised  area,    in 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  41 

the  middle  of  which,  later,  a  scab,  the  size  of  a  pin's  head, 
appears  where  the  epidermis  has  been  damaged.  A  slight  red- 
ness in  the  immediate  neighbourhood  of  the  scarification  is 
usually  still  visible  after  twenty-four  hours,  and  then  disappears, 
leaving  onlv  a  small  brown  scab  on  the  natural  skin  during  the 
next  few  days.  After  the  scab  has  fallen  off  a  fine  pale  scar  is 
visible.  The  intensity  of  the  traumatic  reaction  is  dependent  on 
the  depth  of  the  scarification  and  on  the  individual  reactivity  of 
the  skin  (vide  control  sites  on  Plate  I). 

__„'.*,         .  The  inoculations  with  negative  reaction  give 

The   Negative  .     ,,  &  .,  &,     , 

f  rise  to  the  same  appearance  as  the  control 

ac    on.  site  lying  between  them  :  they  appear  in  the 

first   twenty-four   hours   slightly   swollen.      The   distinction   from 

minimal  specific  reaction  demands  a  certain  amount  of  practice. 

Hence  v.  Pirquet  recommends  the  beginner  to  regard  reactions 

under  5  mm.  in  diameter  as  doubtful,  and  in  such  cases  to  repeat 

the  inoculation,  as  a  positive  reaction  becomes  more  marked  on 

repetition. 

We  can  only  concur  in  this  now  that  Ellermann  and  Erlandsen  have 
proved  that  the  positive  result  of  the  second  cutaneous  inoculation  after  a 
previous  negative  reaction  is  to  be  attributed  to  a  universal  sensitization 
of  the  organism,  but  that  tuberculin  is  not  capable  of  sensitizing  an  organism 
IDerfectly  free  from  tuberculosis. 

_.       _     .  .  The   positive  cutaneous  tuberculin   reaction 

The   Positive 

has    a    latent    period    varying    from    three 

Keaction.  hours  to  several  days ;   in  most  cases  it  is 

well  developed  after  twenty-four  hours,   and  most  distinct  after 

forty-eight.      The   inflammatory,  reaction   caused   by   the   specific 

action   of   the  tuberculin   consists   in   hyperemia  and   exudation, 

and  appears  as  a   slightly   raised   reddening,    starting   from   the 

roughened  spot   of  skin,    and   increasing   rapidly   in   extent  and 

height.     An  inoculation  papule  arises  of  individually  very  various 

extent    and    intensity ;    on    the    average   the    diameter    measures 

about    10   mm.,    occasionally   20   mm.,    and   only    in    exceptional 

cases,  with  very  severe  reaction,  does  it  extend  to  30  mm.     The 

edge  of  the  papule  is  circular  or  irregular,  or  it  may  be  rendered 

indistinct  by  small  follicular  swellings  on  the  margin  ;  in  intense 

reactions  it    is  surrounded   by   a   flat,    slightly  bluish-red   areola 

(vaccinal  area). 

Plate  I  shows  the  appearances  of  a  slight  and  of  a  well- 
marked  cutaneous  reaction. 

The  maximum  of  the  reactive  signs  is  generally  reached 
forty-eight    hours    after    the    inoculation  ;     then    the    exudation 


42  TUBERCULIN    IN   DIAGNOSIS    AND    TREATMENT 

decreases,  the  redness  fades,  passes  over  into  violet,  and  gradu- 
ally into  a  pigmentation  which  may  remain  visible  for  weeks. 
Then  follows  a  slight  peeling  of  the  epidermis. 

From  this  fundamental  type  of  cutaneous  reaction  there  are 
numerous  variations  in  respect  of  latent  period,  development  and 
disappearance. 

Thus  a  reaction  beginning  after  from  six  to  twelve  hours, 

generally    very    weak    and    ceasing   after    twenty-four    hours,    is 

described  as  a  rapid  reaction  ;  it  is  so  very  rare  that  it  is  of  no 

practical   importance.     More  frequently  a  prolonged   reaction   is 

observed,  which  occurs  after  from  six  to  fifteen  hours,  and  remains 

as  a  very  marked  papule  more  than   four   days,    sometimes   for 

weeks  and  months. 

. .  ,   _  If    the    latent    period    exceeds    twenty-four 

Aberrant  Types     .  .    .        ,  f  .  :  .  ,  J  ,. 

hours  it  is  a  late  reaction,  which,  according 

ot   Keaction.  tQ   y^   pjrqUetj    occurs   principally   in   cases 

clinically  unsuspected,  and  only  exceptionally  (torpid  reaction) 
in  manifest  tuberculosis. 

In  respect  of  colour  the  papules  show  the  most  various 
grades;  in  general  they  are  bright  red  in  well-nourished 
subjects  with  healthy  skin  colour,  pale  red  in  anaemic  patients, 
and  colourless  (without  hyperaemia)  or  livid  (without  exuda- 
tion) in  the  last  stage  of  fatal  forms  of  tuberculosis.  In  those 
cases  in  which  the  papule  is  only  recognizable  by  the  sense  of 
touch  or  by  lateral  illumination,  v.  Pirquet  speaks  of  a  cachectic 
reaction. 

Finally  the  scrofulous  reaction  deserves  special  mention,  a 
reaction  observed  by  v.  Pirquet  chiefly  in  scrofulous  children 
and  with  its  small  warty  nodules  in  the  immediate  neighbourhood 
of  the  papule  proper,  reminiscent  of  the  appearance  of  lichen 
scrofulosorum.  Of  such  reaction  we  have  seen  isolated  examples 
in  phthisical  adults. 

If  the  cutaneous  inoculation  is  doubtful  or  negative,  and  is 
then  repeated  after  some  days,  a  positive  reaction  frequently 
appears ;  now  and  then  also  a  late  reaction  at  the  previous  site 
of  inoculation.  This  so-called  secondary  reaction  manifests  itself 
in  v.  Pirquet's  experience  with  children  principally  when  the 
tubercle  cannot  clinically  be  demonstrated,  corresponding  to  the 
torpid  or  primary  late  reaction  already  mentioned. 

The  specific  nature  of  the  cutaneous  tuberculin  reaction,  occur- 
ring as  it  does  only  in  the  organism  infected  with  tuberculosis,  is 
practically  confirmed  by  observations  at  the  bedside  and  -post 
mortem.  Specially  conclusive  in  this  respect  are  the  experiences 
of  v.  Pirquet  [53]  and  Ganghofner  [54]  with  a  large  number  of 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  43 

children,  the  indications  given  by  the  cutaneous  test  being  con- 
firmed by  post-mortem  examination.  Sorgo's  objection  that  the 
cutaneous  reaction  to  tuberculin — just  as  to  other  toxins,  e.g.,  of 
diphtheria,  dysentery  and  cholera — is  to  be  ascribed  to  a  common 
non-specific  cause — an  increased  sensitiveness  of  the  skin  of 
tubercular  individuals — has  been  refuted  by  Zieler's  [55]  accurate 
experiments. 

The  structure,  too,  of  the  papule  points  to  its  origin  in 
a  histological  reaction  of  a  specific  kind.  Daels  [56]  cut  serial 
sections  of  the  papules  of  the  late  reaction  and  found  "  elongated 
nodules  with  central  giant  cells  of  typical  Langhans  form,  and 
with  epithelioid  and  round  cells  at  the  periphery,"  changes  iden- 
tical with  the  specific  structure  of  tubercular  tissue  or  of  the 
tubercle  itself. 

Zieler  [55]  saw  far  beyond  the  sites  of  inoculation  tubercles 
with  typical  Langhans  giant  cells  in  their  blood-vessels  deep 
into  the  subcutaneous  tissue. 

The  tubercular  modifications  at  the  sites  of  inoculation, 
which  are  proved  by  histology,  suggest  the  idea  of  contra-indica- 
tions  of  the  cutaneous  reaction.  On  this  point  very  little  has 
been  written,  and  this  shows  that  only  where  there  is  an  excep- 
tionally high  degree  of  hypersusceptibility  to  tuberculin  can 
existing  scrofulous  changes  appear  more  clearly  or  for  the  first 
time  in  other  parts  of  the  body  (distant  reaction). 

As    a     sequel     to     the     cutaneous     tuberculin     test 
Possible    Mischief    scrofulous       changes       (phlyctenules,       generalized 
from    Reaction         lichen    scrofulosorum)    were    noticed    in    tuberculin 
children,   the   formation  at   the   site   of   inoculation 
of  a   chronic  ulcer  the   size  of  a  pea  in   an  adult   with   scrofuloderma,  also 
changes   in    the   skin    similar   to    scrofuloderma    and    phlyctenular    conjunc- 
tivitis in   scrofulous   children. 

It  has  further  been  established  that  the  cutaneous  inoculation 
has  a  certain  influence  on  the  body  at  large;  but  this  only,  as  a 
rule,  makes  itself  felt  as  fever,  local  reaction,  and  affection  of  the 
general  tuberculin  susceptibility  when,  in  performing  the  inocu- 
lation, incisions  have  been  made  and  the  tuberculin  has  through 
these  reached  the  deeper  layers  of  the  skin  and  thence  the  circu- 
lation. The  rise  of  temperature,  which  in  these  cases  begins  with 
the  development  of  the  papule,  is,  however,  never  high  (about 
20  F.)  nor  of  long  duration.  When  the  platinum  scarifier  is 
used  we  have  never  observed  fever  or  other  symptom  of  general 
reaction. 

The  harmful  results  of  the  cutaneous  test  enumerated  above 
are   numerically — in   comparison   with   the   enormous   number  of 


44  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

reactions   carried   out — so    infinitely    rare    and    in    themselves    so 

insignificant  that  they  hardly   deserve  the   name.        In   fact  the 

cutaneous  tuberculin  reaction,  carried  out  lege  artis  according  to 

v.  Pirquet's  directions,  is  a  diagnostic  method  as  harmless  as  it 

is  easy,  which,  thanks  to  its  simplicity  and  freedom  from  risk,  is 

suitable  for  use  in  the  earliest  childhood,  and  to  which  in  respect 

of  practical  application  no  contra-indication  can  be  raised. 

-  r    ,  The  question,  however,  whether  it  is  neces- 

sarv  before  making  use  of  the  cutaneous  test 
Patient 

to    obtain    the    permission    of    the    patient, 

or  in  the  case  of  children  the  permission  of  the  parents,  is 
answered  by  Bumm  [57]  in  the  affirmative  from  the  legal  point 
of  view.  Even  from  the  point  of  view  of  expediency,  however, 
the  physician  will  do  well  only  to  inoculate  when  a  patient  or  his 
legal  representative  has  actively  or  passively  given  his  assent. 
It  is  allowable  for  the  physician  to  obtain  his  consent  through  a 
third  person  (a  teacher,  for  instance),  or  it  may  be  included  in 
the  general  acceptance  of  the  conditions  of  admission  to  the 
hospital. 

The  indications  are  given  by  the  course  of 
Indications.  the  reaction  and  its  effects.  "The  following 

points  must  be  considered  in  connection  with  these  :  — 

The  specific  nature  of  the  intracutaneous  test  cannot  be  dis- 
puted for  the  same  reasons  as  applv  to  the  specificitv  of  the 
cutaneous  and  percutaneous  reactions. 

The  specific  inflammatory  symptoms  of  the  cutaneous  inocu- 
lation occur  without  accompanving  rise  of  temperature  or  other 
symptoms  of  a  general  reaction ;  they  indicate  the  presence  of 
tuberculosis  in  an  anatomical  sense. 

The   positive   cutaneous    reaction    gives    no 
Positive   Result.      information  as  to  the  sjte  0f  the  disease,  or 

its  activity  or  inactivity.  It  onlv  shows  that  the  body  somewhere 
and  at  some  time  has  been  infected  with  tubercle  bacilli.  Therefore 
not  only  those  manifestly  tubercular  react  but  also  those  who  are 
clinically  non-tubercular.  That  is  specially  important  in  the 
diagnosis  of  adults,  in  whom  the  positive  cutaneous  reaction  alone 
does  not  afford  any'  practical  conclusions  as  regards  treatment. 
With  adults  the  cutaneous  reaction  is  onlv  of  importance  when 
considered  in  conjunction  with  the  clinical  appearance  of  the 
disease.  When  it  is  very  distinctlv  positive,  accompanied  by 
considerable  infiltration  or  extensive  reddening  in  the  vicinity  of 
the  inoculation  site  and  only  slowly  disappears,  then  very 
thorough  examination  and  observation  of  the  patient  is  impera- 
tive. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  45 

The   negative   result  of   the   test   speaks   in 
Negative 

6  general    for    the    absence    of    tuberculosis. 

Kesult.  gut   tne   reaction   may   faii   j[n   Spite  of   the 

presence  of  actual  tuberculosis  capable  of  clinical  demonstration. 
This  is  then  to  be  explained  by  the  nature  of  the  tubercular 
process  (fungoid,  fistulous,  or  suppurating),  by  the  local  or 
constitutional  condition  of  the  inoculated  subject  (condition  of 
the  skin,  general  cachexia),  by  tuberculin  immunity  after  specific 
treatment,  or  by  other  circumstances,  e.g.,  during  measles,  the 
incubation  stage  of  scarlet  fever,  the  continuance  of  high  inter- 
mittent fever,  and  in  pregnancy. 

According     to     v.     Pirquet     the     absence     of    any 

In    Measles   and       cutaneous   reaction   during  measles,    as   well   as   in 

in    PreffnanCV  miliary   tuberculosis,    is    caused  by  the    absorption 

of  the  ergins  (the  bodies  which  bring  about  the 
clinical  reaction  between  the  tuberculin  and  the  cells).  "  Considered  in  this 
light  the  decrease  in  the  tubercular  allergia  during  measles  is  brought  into 
harmony  with  the  fact  that  in  connection  with  the  disease  there  so  often 
occurs  a  dissemination  of  tuberculosis."  In  the  same  way  Stern  explains 
the  decrease  in  activity  of  the  cutaneous  reaction  during  pregnancy  to  the 
fixation  of  the  antibodies  to  the  lipoids  of  the  placenta  or  of  the  blood. 
In  the  same  way  can  be  explained  the  unfavourable  effect  of  pregnancy  on 
patients  suffering  from  tuberculosis. 

,   .      r,  .      Roily     [58!     has     also     at     various     times 

and  in   Pneumonia,  J      LU  J., 

.  systematically  tested  the  powers  of  reaction 

"  '        "      to  tuberculin  of  the  skin  of  patients  suffering 

from  croupous  pneumonia,  enteric  fever,  diphtheria,  erysi- 
pelas, polyarthritis  rheumatica,  and  angina  follicularis.  He 
discovered  that  in  the  majority  of  cases  during  the  course  of  these 
diseases  a  negative  condition  persists,  while  a  distinctly  positive 
reaction  is  obtained  during  convalescence.  He  considers  the 
reason  of  this  change  in  the  same  individual  to  lie  in  general  not 
in  special  immunizing  processes,  but  more  probably  locally  in  a 
changed  condition  of  the  skin.  We  are  of  the  same  opinion,  and 
also  agree  with  Roily  that  the  skin  may,  under  various  conditions, 
be  very  slightly  or  not  at  all  allergic,  but  that  the  organism,  on 
the  contrary,  may  at  the  same  time  be  very  susceptible  to 
tuberculin. 

Non-appearance  of  The,  cut*neous    reaction    regularly   falls    in 
_.        ,.        .  the  last  days  of  a  fatal  case  of  tuberculosis, 

Reaction  in  •,        ,,  ,.  ,    ,  .     _,, 

when  the  reacting  power  of  the  patient  has 

Moribund  Cases,  become  non-existent  either  by  becoming- 
accustomed  to  the  tubercular  virus,  or  in  consequence  of  cachexia. 
It  often  fails  in  cases  with  hematogenous  extension  of  the  process, 


46  TUBERCULIN   IN   DIAGNOSIS   AND   TREATMENT 

in  miliary  tuberculosis  and  tubercular  meningitis;  in  severe  cases 

of  the  last  two,  repeated  inoculations  of  the  same  patient  may  even 

give  varying  results.     The  cutaneous  reaction  seldom  fails  where 

tuberculosis  occurs  along  with  some  other  disease ;  in  this  case  the 

late  reaction  acquires  a  certain  importance  in  the  diagnosis  whether 

it  appears  late  after  the  first  inoculation  or  only  becomes  positive 

on  a  repetition  of  the  test. 

The    knowledge     of     the     non-appearance     of     the     positive 

cutaneous  reaction  in  spite  of  the  presence  of  tuberculosis  leads 

us  in  such  cases  to  abandon  cutaneous  inoculation  altogether  from 

the  very  first,  or  at  least  to  be  very  cautious  in  our  estimate  of 

the  result. 

,^.  ,-     /-v     ,   ■   j_    Apart  from  these  exceptions  and  the  failure 

Diagnostic  Certainty     ^  ,.rr  .        .  .  ... 

.to  differentiate  between  active  and  inactive 

tubercular  processes,  the  diagnostic  cer- 
tainty of  the  cutaneous  reaction  is  in  other  respects  great.  From 
our  own  experience  the  cutaneous  reaction  with  undiluted  tuber- 
culin was  positive  in  96  to  98  per  cent,  of  adult  tubercular  patients 
[59].  This  percentage  decreases  in  cases  in  the  third  stadium  of 
the  disease.  Other  statistics  show  similar  results,  especially  those 
of  v.  Pirquet  for  children  :  97  per  cent,  of  the  positive  reactions 
showed  undoubted  naked-eye  appearances  of  tuberculosis  at  the 
autopsy,  whereas  all  the  children  who  were  found  on  the  post- 
mortem table  to  be  free  from  tubercle  had  given  a  negative 
reaction. 

_  .  From   the   prognostic   point   of   view,    cuta- 

Prosrnosis 

&  '  neous  inoculation  is  of  little  value,  and  only 

to  be  considered  in  conjunction  with  the  results  of  the  clinical 

examination,    any    possible    complications,     hygienic    conditions 

and  other  external  circumstances.     Considered  by  itself,   neither 

a  positive  nor  a  negative  cutaneous  tuberculin   reaction  justifies 

prognostic     conclusions.       On     the     other     hand     the     repeated 

failure   to    obtain    a    cutaneous    reaction    in    obvious    tuberculosis 

generally  points  to  a  bad  prognosis  and  that  often  at  an  earlier 

period    than     the    clinical     examination.     And     a     well-marked 

positive   cutaneous    reaction   can   be   looked    upon    as   an    almost 

certain    "  indication   of  the   power   to   tight   against   the   tubercle 

bacillus."     That    is    to    say,    when    it    is    attained    with    diluted 

tuberculin    it   aids    in    making   a    relatively   favourable   prognosis 

of    the    course    of    a    case    of    manifest    tuberculosis.     Whether 

repeated    graduated    inoculations    at    long    intervals    have    any 

prognostic  significance  is  still  doubtful.     It  is  probable  that  an 

increased    and    more    rapid    cutaneous    reaction    is    general    in 

favourable   clinical   improvement   of   active   tubercular  processes, 

just    as    high    cutaneous    reactivity    of    patients    not    undergoing 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  47 

specific  treatment  usually  goes  hand  in  hand  with  favourable 
general  condition  and  large  content  of  antibodies.  On  the  other 
hand,  the  graphic  record  of  the  course  of  the  reaction — normal, 
rapid,  prolonged  reaction — is  of  no  assistance  in  prognosis,  not 
even  to  distinguish  active  from  inactive  tuberculosis. 

Qln  order  to  distinguish  active  processes  of 
uantitative         ,  ,  ,        •  r  •       .•         t?u  , 

tuberculosis   from   inactive,    hllermann   and 

es  Erlandsen     [61]     have    experimented    with 

the  quantitative  method  of  cutaneous  inoculation,  using  graduated 

concentrations  of  tuberculin. 

For  these  very  finely  graduated  inoculations  they  chose  concentrations 
of  a  standard  tuberculin  of  oT  per  cent,  rising  to  50  per  cent,  and  noted 
the  dilution  which  produced  absolutely  no  cutaneous  reaction.  The  re- 
ciprocal value  of  this  tuberculin  dilution  is  then  a  measure  of  the  power 
of  reaction,  the  "  tuberculin  titre  of  the  organism." 

According  to  the  experiments  of  Erlandsen  and  Petersen  [60],  the 
tuberculin  titre  should  be  o  in  persons  free  from  tuberculosis,  it  should 
remain  below  100  when  the  tuberculosis  is  inactive,  and  rise  to  200-400  when 
active  tuberculosis  is  present.  It  should  go  back  to  below  100  when  the 
tuberculosis  has  become  inactive  and  drop  sharply  a  short  time  before 
death.  Only  in  cases  of  tuberculosis  of  the  glands  and  bone  would  there 
be  generally  a  high  tuberculin  titre  for  a  very  long  time.  Although  one 
cannot  diagnose  tuberculosis  from  such  estimations  alone,  yet,  in  conjunc- 
tion with  other  clinical  aids,  a  high  tuberculin  titre  supports  the  diagnosis 
of  active,  and  a  low  titre  the  diagnosis  of  inactive,  processes  of  tuberculosis. 

Erlandsen  [61]  has  lately  drawn  up  a  table  for  calculating  the  tuber- 
culin titre.  The  breadth  in  millimetres  of  a  papule  corresponding  to  a  4  per 
cent,  tuberculin  solution  (pj  and  the  difference  in  the  breadth  of  this  papule 
in  millimetres  after  twenty-four  and  forty-eight  hours  (d  )  are  determined. 
The  tuberculin  titre  can  then  be  read  off  from  the  table. 

Lossen,  S.  Moller,  Mirauer,  Wallerstein,  Waltershofer,  and  others  have 
come  to  the  conclusion  from  their  own  experiments  that  graduated  tuber- 
culin concentrations  are  of  no  practical  use  in  distinguishing  active  and 
inactive  tuberculosis. 

We  also,  from  our  own  experience  with  quantitative  cutaneous 
tuberculin  tests,  must  reserve  our  opinion  and  cannot  recommend 
them  in  practice.  The  idea  that  the  cutaneous  reaction  can  only 
be  useful  in  the  case  of  adults  when  graduated  doses  of  tuberculin 
are  used  may  be  excellent,  but  the  method  of  applying  it  is  open 
to  too  many  inexactitudes  and  inaccuracies  to  be  reliable.  More- 
over, we  are  dealing  with  conditions  of  great  hypersusceptibilitv 
which  are  characterized  by  too  great  individual  variations  and 
do  not  give  reliable  information  for  the  diagnosis  of  the  nature 
of  the  tuberculosis. 

For  this  reason  we  do  not  consider  the  method  recommended 
by  Ditthorn  and  Schultz  [62]  of  cutaneous  inoculations  with 
iron  tuberculin  (iron  precipitates  of  tubercle  bacillary  substance) 


48  TUBERCULIN   IN    DIAGNOSIS    AND   TREATMENT 

to    be    promising    in    the    differentiation    of    active    and    inactive 

tuberculosis.     Schellenberg  [63]  confirms  this  on  the  ground  of 

detailed  experiments ;  the  strong  positive  iron-tuberculin  reaction 

is  not  a  guide  to  activity  or  inactivity  of  the  disease ;  and  the 

assertion  that   iron  tuberculin  does  not  call  forth  a  reaction   in 

latent   or    inactive   tuberculosis    is    incorrect. 

^  ...      ..  ^      The    general    verdict    as    to    v.     Pirquet's 

General  Verdict  ,.  ,  , 

cutaneous    reaction    may    be    expressed    in 

the  most  general  form  conceivable:  Its 
Cutaneous  Test,  application  may  be  extended  to  all  the 
circumstances  of  general  and  hospital  practice,  for  it  is  extremely 
simple  for  the  physician  and  can  be  used  at  any  time  in  con- 
sultation hours,  and  also  in  the  case  of  feverish  patients  and  those 
in  bed.  It  is  a  perfectly  harmless  action,  involving  no  danger 
and,  carried  out  lege  artis  according  to  v.  Pirquet's  direction, 
works  without  causing  any  malaise,  fever,  local  or  general 
disturbance  or  complications  of  any  kind. 

The  real  scientific  and  practical  importance  of  the  cutaneous 
tuberculin  test  is  certainly  limited  to  early  childhood,  to  the  first 
two  or  three  years  of  life.  Here  it  triumphantly  proves  itself  to 
be  a  great  and  genuine  discovery.  It  may  also  be  successfully 
used  in  the  investigation  of  tuberculosis  in  children  of  school 
age  and  leads  to  suitable  hygienic  prophylactic  measures  for  the 
protection  of  the  rising  generation  at  home,  in  public,  at  school, 
&c.  It  is  a  diagnostic  medium  par  excellence  in  children's 
practice,  to  which  we  will  return  later  in  a  special  chapter.  But 
it  is  also  true  here  that  only  the  clinical  condition  in  conjunction 
with  the  cutaneous  reaction  must  decide  as  to  the  treatment  of 
the  individual  case. 

In  veterinary  practice  the  cutaneous  test  is  of  no  practical 
importance. 

Detre's  ^n    or<^er    to    differentiate    cases    of    tuber- 

r^.rc         ..   ..  r   culosis    Detre    [64]    modified    v.    Pirquet's 

Differentiations  of  ,     ,    ,  •  ,  ,.«•  1  •    1 

method   by   using   three   different   kinas   ot 

'  tuberculin    for    the    cutaneous    inoculation  : 

Modified  Test.       ^    Koch's  old   tuberculin;    (2)   the   filtrate 

from   a   culture   of   human   tubercle  bacilli;    (3)   the   filtrate   of  a 

bovine  culture.     According  to  the  appearance  of  the  individual 

papules  he  then  divides  the  cases  into  those  susceptible  to  human 

and  those  susceptible  to  bovine  bacilli.     In  this  way  Detre  thinks 

it  possible  to  come  to  a  decision  as  to  the  nature  of  the  infecting 

virus,  and  that  the  organism  will   react  most  powerfully  to  the 

toxin   of  that  type  of  bacilli   which   has   infected   it.     According 

to   the   results   obtained   by    Detre,    pulmonary    tuberculosis,    for 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  49 

instance,  showed  a  preponderating  reaction  (more  than  90  per 
cent.)  to  human  bacilli,  but  visceral  and  surgical  tuberculosis 
to  bovine  (30  to  50  per  cent.),  so  that  it  appears  to  him  that 
the  human  type  of  tubercle  bacillus  is  specially  suited  for 
pulmonary  tuberculosis  and  the  bovine  bacillus  for  tuberculosis 
of  the  bones  and  glands. 

v.  Gebhardt  also  saw  a  preponderating  reaction  of  the  bovine 
type  in  surgical  tuberculosis  and  of  the  human  type  in  internal 
tuberculosis.  On  the  other  hand,  according  to  Schroder,  patients 
suffering  from  pulmonary  tuberculosis  always  react  cutaneously 
at  the  same  time  to  bovine  and  human  tuberculin,  to  the  latter 
generally  more  severely.  Similar  observations  in  adult  tuber- 
culosis were  made  by  Friedrich,  Laszlo,  Raw,  the  authors,  and 
others.  In  consideration  of  these  results  and  the  now  undisputed 
fact  that  human  pulmonary  tuberculosis  is,  with  very  few  ex- 
ceptions, to  be  ascribed  to  an  infection  with  tubercle  bacilli  of 
the  typus  humanus,  we  cannot  accept  Detre's  statement  that 
about  every  tenth  case  is  etiologically  of  bovine  origin. 

But  this  does  not  affect  the  observation  made  by  Monti, 
Heim,  John,  v.  Gebhardt  and  others,  that  cases  of  internal  and 
surgical  tuberculosis,  especially  in  children,  react  cutaneously 
in  varying  degree  both  to  tuberculin  in  general,  and  also  to 
various  kinds  of  tuberculin.  This  is  because  the  surgical  tuber- 
culosis of  greater  cutaneous  reactivity  offers  greater  resistance 
and  defence  against  the  tubercle  bacillus  and  is  therefore  more 
favourable  as  regards  prognosis  than  internal  tuberculosis.  The 
difference  of  time  in  growth  on  culture-media  of  human  and 
bovine  bacilli  may  also  cause  differences  in  the  reaction  ;  on  this 
fact  depends  the  observation  first  made  by  Carl  Spengler,  that 
bovine  toxins  are  far  less  toxic  for  tubercular  patients  than  the 
human.  Thus  it  is  only  a  question  of  quantitative  differences  in 
a  group  reaction  which  as  such  do  not  permit  of  differential 
diagnostic  conclusions.  Lastly,  differences  may  be  caused  by  the 
scarifications  being  of  unequal  depth,  by  the  effect  of  the  tuber- 
culin in  question  not  always  lasting  the  same  length  of  time,  by 
the  conditions  of  absorption  not  being  the  same,  and  so  on.  On 
the  whole,  we  do  not  hope  for  much  practical  success  from  a 
differential  cutaneous  test. 

(b)  Percutaneous  Tuberculin  Test  of  Moro. 

The  absorption  of  tuberculin  through  the  skin,  introduced 
by  Carl  Spengler  for  therapeutic  purposes,  has  been  also  utilized 
for  diagnosis  by  Moro  and  Doganoff  [65]. 

4 


50  TUBERCULIN   IN   DIAGNOSIS   AND   TREATMENT 

Moro  [66]  recommends  the  inunction  of  a  tuberculin  oint- 
ment consisting  of  equal  quantities  of  Koch's  old  tuberculin  and 
anhydrous  lanolin. 

B     Tuberculini  Kochi  5'o  grm. 

Lanolini    anhydrici  ■••     S'o     ,, 

M.  fiat  ung. 

Sig. — Tuberculin  ointment  for  physician's  own  use. 

In  the  preparation  of  the  ointment  care  must  be  taken  that  the  lanolin, 
which  of  all  vehicles  allows  of  the  greatest  concentration  of  the  ointment, 
should  be  heated  to  200  to  300.  The  ointment,  which  when  fresh  is  of  a 
pale  yellow  colour,  becomes  somewhat  darker  after  a  time,  but  if  stored 
in  a  refrigerator  remains  potent  for  months.  For  each  inunction  a  piece  the 
size  of  a  pea  only  is  used,  so  that  10  grm.  of  the  ointment  suffice  for  some 
100  tests. 

For  practical  purposes  it  is  advisable  to  obtain  the  ointment 
in  small  tubes  containing  2  gr.  Moro's  attempt  to  apply  tuber- 
culin plaster  to  the  skin  has  not  proved  successful  in  practice,  as 
the  necessary  concentration  of  tuberculin  deprived  the  plaster  of 
its  adhesiveness. 

As  site  for  inunction,  Moro  recommends  the 
Method.  abdominal  wall  beneath  the  ensiform  carti- 

lage, or  the  skin  of  the  chest  in  the  neighbourhood  of  the  nipple, 
and  states  emphatically  that  the  skin  of  the  fore-arm  is  unsuit- 
able. Inunction  is  carried  out  with  moderate  pressure  of  the 
finger ;  a  protective  rubber  finger-stall  is  not  necessary,  for  a 
reaction  never  takes  place  on  the  palmar  surface  of  the  finger 
used  for  inunction  purposes.  The  duration  of  the  inunction  is 
half  to  one  minute,  the  diameter  of  the  area  about  5  cm.  After 
the  inunction  the  part  should  be  left  exposed  for  a  few  seconds; 
no  dressing  is  necessary. 

T  The  positive  percutaneous  reaction  appears 

.  in      different      grades     analogous     to     the 

cutaneous  reaction.  We  see  in  adults  and 
children,  as  slightest  grade,  single  or  numerous,  isolated,  more 
or  less  distinct,  reddened  spots,  which  are  only  visible  on  the 
most  careful  inspection  and  disappear  in  a  few  days — miliary 
reaction  (see  Slight  Percutaneous  Reaction,  Plate  I).  We 
observe  as  well-marked  reactions  papules  indistinguishable  in 
degree  of  hyperemia  and  exudation  from  those  of  the  cutaneous 
inoculation — confluent  reaction.  And  we  see,  on  an  inflamed 
base,  red  nodules  arise,  which  sometimes  have  at  the  head  a 
vesicle  filled  with  turbid  matter — vesicular  reaction  (see  Well- 
marked  Percutaneous  Reaction,   Plate  I).     Intermediate  to  these 


THE   SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  5 1 

are  combinations  of  the  individual  reactions.  The  more  severe 
reactions,  which  are  not  always  limited  to  the  site  of  the  inunction 
(disseminated  distant  reaction),  are  generally  accompanied  by 
itching  and  last  several  days,  then  gradually  fading  with  slight 
peeling  and  pigmentation  of  the  skin. 

The  percutaneous  reaction  generally  takes  place  after  twenty- 
four  to  forty-eight  hours,  but  as  it  also  sometimes  appears  after 
three  to  four  days,  the  patients  must  remain  under  observation 
more  than  two  days. 

Of  the  specific  nature  of  the  percutaneous 
Specific  Nature.      reactjon   there   is  as   little  doubt  as  of  the 
cutaneous. 


This  is  not  in  any  way  affected  by  the  observations  made  by  Mory, 
Kanitz,  and  other  writers, ,  that  in  purpura,  epilepsy,  chorea,  and  herpes 
.zoster,  the  percutaneous  as  well  as  the  cutaneous  test  frequently  gave,  even 
in  clinically  unsuspicious  cases,  positive  results.  All  these  cases  have,  at 
some  time  or  other  in  their  lives,  got  the  better  of  a  tubercular  infection, 
and  the  positive  reactions  signify  no  more  than  that  those  illnesses  often 
attack  individuals  infected  with  tuberculosis. 


The  indications  for  the  percutaneous  tuberculin  test  depend 
upon  the  question — whether  it  is  harmless  and  free  from  danger 
and  whether  its  results  are  sufficiently  reliable  to  be  valuable 
for  the  purposes  of  diagnosis.  The  literature  now  existing  on 
this  subject  is  sufficient  to  clear  the  matter  up. 

Moro  tested  the  percutaneous  skin  reaction  on  the 
Diagnostic  large    number    of    child-patients    in    the     Munich 

Value  University  Children's  Hospital  and  Polyclinic,  with 

the  result  that  of  the  manifestly  tubercular  children 
17  per  cent,  did  not  react;  these  were  principally  children  with  miliary 
tuberculosis  and  meningitis,  whilst  all  cases  with  negative  percutaneous 
reaction  were  seen  in  the  'post-mortem  rooms  to  be  macroscopically  free  from 
tuberculosis.  Comparative  investigations  of  the  percutaneous  and  cutaneous 
tests  revealed  a  striking  parallelism,  not  only  in  the  general  results  of  the 
tests,  but  also  in  all  the  minute  details  of  the  reactions.  The  inunction  test 
is  on  the  whole  somewhat  less  sensitive  both  in  manifest  cases  of  tubercu- 
losis and  in  cases  not  clinically  suspect.  This  is,  however,  of  no  real 
advantage,  because  the  limitation  is  small  in  childhood,  and  ceases  after 
the  age  of  from  10  to  12. 

In  cases  of  surgical  tuberculosis  Moro  observed  almost  always  a 
strikingly  intense  reaction,  whilst  these  were  not  usual  in  cases  of  pro- 
nounced scrofula.  In  the  first  six  months  cf  life  the  percutaneous  reaction 
was  so  frequently  negative  in  spite  of  existing  tuberculosis,  that  also  at 
this  period  of  life  it  cannot  be  made  use  of  with  any  certainty  in  opposition 
to  the  clinical  diagnosis. 


52  TUBERCULIN  IN  DIAGNOSIS  AND  TREATMENT 

The  disadvantages  of  the  percutaneous  test 
Disadvantages.       i-e  -n  ^  fact  that  tjie  more  severe  reactions 

set  up  rather  violent  irritation  and,  especially  in  scrofulous 
children,  show  a  tendency  to  spread  also  to  other  parts  of  the 
body.  Disseminated,  grouped  or  girdle-shaped  reactions  in 
distant  parts  of  the  skin,  lichen  scrofulosorum,  also  general 
exanthema  have  been  observed. 

According  to  the  observations  of  Emmerich,  Wetzell,  Heine- 
mann,  Bullinger  and  others,  the  inunction  reaction  is  of  more 
value  clinically  for  children  than  for  adults,  in  whom  it  also 
indicates  inactive  foci. 

Adult  tubercular  patients  with  atrophic  skin  may  give  a  negative 
reaction  to  the  first  inunction  and  a  positive  to  the  second  if  greater 
pressure  is  applied,  lasting  more  than  one  minute.  Control  inunctions  with 
ung.  ciner.,  soft  soap  ointment,  chrysarobin,  lenigallol  and  other  oint- 
ments have  given  quite  negative  results,  except  in  patients  with  very 
delicate  skin  and  exceptionally  strong  dermography. 

We  have  employed  the  three  tests  (cutaneous,  conjunctival,  and  per- 
cutaneous) simultaneously  on  ioo  cases  of  definite  cases  of  adult  tuberculosis 
in  all  stages,  and  have  obtained  the  most  varied  results.  Sometimes  all 
three  reactions  were  positive,  sometimes  two,  sometimes  only  one.  The 
percutaneous  test  on  the  inner  side  of  the  fore-arm,  after  rubbing  the  skin 
with  ether,  gave  the  fewest  positive  reactions. 

From  this  it  is  clear  that  the  percutaneous  test  is  decidedly 

inferior  to  the  cutaneous   in   point  of  definiteness.     This  seems 

readily  intelligible  when   we  consider  that  the  condition   of  the 

skin — thickness  of  the  epidermis,   number  and  size  of  the  pores, 

amount  of  moisture,  excitability  of  the  nervous  system — must  have 

an  essential  bearing  on  the  result  of  the  test.     Where  the  skin  is 

thick,  dry,  scaly  or  atrophic,  the  inunction  test  is  useless,  even 

when  the  other  conditions  for  the  occurrence  of  the  reaction  are 

present.     Moreover,   the  duration  and  intensity    of    the    friction 

play  an  important  part.     All  these  external  influences  must  have 

much  more  influence  here  than  in  the  cutaneous  test,  where  the 

possibility    of   the    undiluted   tuberculin    acting    is,    to    a    certain 

degree,   guaranteed  by  the   injury  to   the  skin.     It  also  follows 

from  this  that  the  percutaneous  test  cannot  be  preferred  to  the 

cutaneous  for  indicating  activity  in  the  tubercular  foci. 

_        ,      .  There  are  no  contra-indications  to  the  per- 

Conclusions.  .  .   ,  ,.  .       ,, 

cutaneous    tuberculin    test,    except    in    the 

case  of  pronouncedly  scrofulous  children,  when  there  is  a  danger 

of  distant   reactions  or  general   exanthema. 

From  the  positive  result  of  the  inunction  the  presence  of  a 

tubercular    focus,    though    it    may    be    without    any    importance 


THE   SPECIFIC   DIAGNOSIS    OF   TUBERCULOSIS  53 

whatsoever,  may  be  concluded,  without  information  as  to  the 
locality,  the  active  or  inactive  character  of  the  infection. 

If  the  reaction  be  negative,  this  does  not  in  any  way  prove 
the  absence  of  tuberculosis.  It  almost  regularly  fails  in  early 
infancy,  in  cases  with  hematogenous  diffusion  of  the  process 
(meningitis,  miliary  tuberculosis)  and  during  measles,  sometimes 
also  in  cachectic  patients,  even  when  the  presence  of  tuberculosis 
has  been  clinically  clearly  demonstrated.  This  happens  so  fre- 
quently in  the  case  of  definitely  tubercular  adults  that  express 
warning  must  be  given  against  attaching  any  value  to  negative 
results  of  the  inunction  test  in  diagnosis  in  the  case  of  adults. 

The  value  of  the  percutaneous  tuberculin  test  in  diagnosis 
is  therefore  much  greater  in  children,  except  during  the  first 
six  months  of  life,  than  in  adults.  A  positive  reaction  in 
children  points  with  much  more  probabilitv  to  the  presence  of 
active  tuberculosis. 

It  can  therefore  be  employed  instead  of  the  cutaneous  reaction 
when  the  latter  is  not  allowed  from  fear  of  "  inoculation."  It  is 
also  to  be  recommended  when  the  physician  does  not  wish  to 
declare  his  suspicion  of  tuberculosis  to  the  child's  parents.  In 
this  case,  a  small  portion  of  the  child's  skin  can  easily  be  rubbed 
with  the  ointment  on  some  pretext  or  other. 

The  tuberculin   inunction   test  has  no  value  in  prognosis. 

The   methods   recommended  by    Lignieres   and   Lautier   are 

merely  modifications  of  Moro's  inunction  test. 

Lignieres'  Lignieres    [67]    rubs    into    the    well-shaven 

..     .._       .  skin    five   to   six   large'  drops   of   undiluted 

Modification.        ,    ,  ,■     r  .  °  „7.lL. 

tuberculin  for  one  to  two  minutes.     Within 

one  or  two  days,  if  the  patients  are  tubercular,  there  arise  isolated 

or  partly  or  entirely  confluent  papules,  in  children  sometimes  in 

two  or  more  sets. 

Lignieres'  modification  does  not  seem  to  us  to  possess  any 

advantages.     It  has,   on   the  other  hand,  a  disadvantage  not  to 

be  made  light  of.     There  exists  the  possibility  that   the  use  of 

the  razor  may  produce  superficial  lesions  of  the  epidermis,  and 

therewith  the  danger  that  an  altogether  uncontrollable  quantity 

of  the  "  five  or  six  large  drops  of  undiluted  tuberculin  "  mav  be 

absorbed  and  produce  a  general  reaction.     We,  therefore,  reject 

it  as  superfluous  and  harmful. 

Lautier's  Lautier     [68]     places    a     swab     of    cotton- 

..     ..»       .  wadding,    soaked   with   two   or  three   drops 

Modification.  r    T  .      ,   ,  ,.  t,  r 

ot    1    per    cent,    tuberculin,    on    the    outer 

surface  of  the  arm  without  any  previous  preparation  of  the  skin, 


54  TUBERCULIN   IN   DIAGNOSIS    AND   TREATMENT 

and  fastens  it  on  with  a  bandage.  After  twenty-four  to  forty- 
eight  hours  this  produces  in  tubercular  patients  an  inflammatory 
redness.     We  consider  this  modification  also  to  be  unreliable. 

(c)  Intracutaneous  Tuberculin  Test. 

Mendel  [69]  noted  in  tubercular  patients  after  intracutaneous 
injection  of  quite  small  quantities  of  tuberculin  a  characteristic 
local  reaction  due  to  hypersusceptibility,  but  he  could  not  study 
it  further  for  want  of  clinical  material.  This  was  done  later  by 
Moussu,  Mantoux  and  Roux,  who  recommended  the  "Intra- 
dermal  Reaction  "   for  the  diagnosis  of  tuberculosis. 

Independently  of  these  French  authors,  van  Balen  and  later 
Moller  have  used  the  method,  employing  varying  concentrations 
to  obtain  information  as  to  the  reactivity  of  tubercular  affections. 
According-  to  Mantoux  and  Roux  r7ol,  the 
intracutaneous  tuberculin  test  is  carried  out 
as  follows:  One  drop  of  a  dilution  of  old  tuberculin,  1  : 5,000 
(=  '01  c.mm.)  is  injected  into  the  whole  thickness  of  the  skin. 
After  taking  up  a  fold  of  the  skin  of  the  anterior  surface  of  the 
thigh,  the  fine  sterile  needle  of  a  Pravaz  syringe  is  inserted  almost 
parallel  to  the  surface,  care  being  taken  that  the  point  of  the 
needle  after  the  puncture  is  directed  rather  upwards  (epidermis) 
than  downwards  (hypodermis).  The  injection  has  been  success- 
ful if  it  is  immediately  followed  by  the  formation  of  an  cedematous 
nodule  of  about  4  mm.  in  diameter,  which  disappears  after  a  few 
minutes. 

The  solution  required  for  the  intracutaneous  test  as  suggested  by 
Mantoux  and  Roux  is  prepared  by  mixing  1  c.c.  of  1  per  cent,  tuberculin 
with  49  c.c.  normal  saline  immediately  before  the  injection.  A  single 
drop  of  this  solution  must  be  injected  into  the  cutis. 

We  will  not  describe  the  technique  of  the  intracutaneous  test 
as  specially  difficult ;  however,  it  does  not  seem  altogether  an 
easy  matter  to  allow  exactly  one  drop  to  fall  from  the  needle 
lying  in  the  tissues  and  to  perform  the  test  entirely  intra- 
cutaneously.  For  when  the  injection  is  made  in  the  subcutaneous 
tissue,  febrile  symptoms  may  occur. 

The   method   suggested   by    Engel    [71]    is 

°  "     simpler,   less  painful,   and  practicable  even 

with  restless  children  :  the  puncture  is  made  with  a  very  fine, 
short  needle,  flat  in  the  skin  on  the  back  of  the  fore-arm  and  by 
pressure  on  the  piston  of  the  svringe — a  small. wheal  about  the 
size  of  a  lentil  is  produced.     The  white  wheal  disappears  in  about 


THE  SPECIFIC    DIAGNOSIS    OF   TUBERCULOSIS  55 

a  quarter  of  an  hour,  and  except  for  the  puncture  hole  there 
remains  nothing  to  be  seen  until  the  intracutaneous  reaction  takes 
place  (Plate  I).  Engel  makes  the  test  in  the  first  place  with  a 
tuberculin  dilution  of  i  :  5,000  and  repeat  it  if  the  result  is 
negative.  He  raises  the  concentration  to  1  : 1,000,  then  to  1  :ioo 
and  finally  to  1  :  10. 

A  positive  reaction  takes  place  in  five  to 
Positive  Result.  g-x  jlours  -m  t^e  form  0f  infiltration,  per- 
ceptible to  touch  or  sight.  After  twenty-four  hours  the  infiltration 
is  increased,  reddish,  sometimes  cedematous,  with  an  erythema- 
like edge.  It  reaches  its  highest  point  in  the  course  of  forty- 
eight  hours.  The  extent  and  intensity  of  the  reaction  vary  in 
different  individuals.  In  some  small  red  papules  are  formed,  while 
in  others  their  diameter  measures  15  or  20  mm.  Also  pronounced 
infiltration  extending  over  a  surface  as  large  as  the  palm  of  the 
hand,  with  inflammatory  reddening  and  swelling  of  the  surround- 
ing tissue  and  blister  formation  in  the  centre,  sometimes  occurs 
(Plate  II). 

In  another  two  days  the  reaction  gradually  diminishes, 
sometimes  with  scaling  of  the  skin ;  it  is,  however,  generally 
visible  for  several  weeks.  Mantoux  states  that  in  a  positive 
reaction  there  are  "  hardly  any  general  symptoms  "  ;  very  slight 
fever  may  occasionally  be  noted.  Engel  describes  the  un- 
pleasantness for  the  patient  by  his  method  as  "  minimal," 
especially  as  febrile  symptoms  never  occur.  After  our  experi- 
ences with  adults  we  cannot  agree ;  even  slight  reactions  cause 
discomfort  lasting  for  days,  at  any  rate  irritation  and  itching. 
The  more  severe  reactions  considerably  limit  the  utility  of  the 
arm,  pain  in  the  arm  and  axilla  not  seldom  being  present;  we 
have  also  repeatedly  found  glandular  swellings  as  a  sign  of  a 
tubercular  focal  reaction. 

If  the  test  is  negative,  there  appears  only 
Negative  Results.  a  smau  induration  with  slight  telangiectasis 
or  slight  blue-brown  coloration,  phenomena  which  have  quite 
disappeared  in  two  or  three  days.  As  a  positive  reaction  would 
by  this  time  have  reached  its  height,  mistakes  in  the  judgment 
of  the  intracutaneous  test  are  practicallv  excluded. 

According    to     Mantoux     [72],     the    intra- 

Mantoux.  ,  L  • .    .,  .     ,  c    ..       r  .,      ,       , 

cutaneous  is  the  most  definite  of   the  local 

tuberculin  tests.     If  the  result  is  negative,  tuberculosis  may  with 

certainty  be  assumed  to  be  absent  unless  the  patient  is  cachectic 

or  suffering  from  measles  in  the  incubatory  stage.     On  the  other 

hand  a  positive  result  proves  the  presence  of  tuberculosis  in  the 

body  of  the  patient. 


56  TUBERCULIN  IN  DIAGNOSIS  AND  TREATMENT 

Monti  [73],  who  has  made  the  test  on  374 

children    exactly    according    to    Mantoux's 

directions,  recommends  it  for  general  practice  when  the  cutaneous 

test  has  given  a  negative  result  :   the  possible  presence  of  latent 

tuberculosis  will  then  be  recognized. 

Engel  [71]  considers  the  greatest  advantage 
tngel.  0f  ^e  test  tQ  j-e  jn  tjie  £act  t^at  ^y.  empi0y„ 

ment  of  varying  strengths  of  tuberculin,  even  the  highest  concen- 
trations, the  reaction  can  be  produced  under  all  circumstances. 
Provided  the  necessary  rise  of  concentration  is  observed,  no  case 
which  gives  a  negative  test  can  harbour  tubercular  foci.  There- 
fore the  intracutaneous  reaction  offers  the  security  of  discovering 
tuberculosis  when  the  tuberculin  susceptibility  of  the  organism  is 
reduced  by  acute  infections,  cachexia  or  hematogenous  extension 
of  the  tubercular  infection  ;  it  is  of  assistance  where  the  cutaneous 
reaction  has  its  natural  limits.  It  is  further  applicable  in  febrile 
conditions  and  when  miliary  dissemination  is  suspected,  thus  in 
cases  where  the  subcutaneous  test  is  strongly  contra-indicated. 

The    intracutaneous    reaction    is    indicated 

l  na  l0ns■  when    the    cutaneous    test    is    negative    or 

gives  no  reliable  result ;  also  when  there  are  objections  to  the 
subcutaneous  test  and  when  extreme  certainty  is  necessary  in 
excluding  tubercular  infection  from  the  diagnosis. 

Roemer  and  Joseph  [74]  also  consider  possible  the  quantita- 
tive estimation  of  hypersusceptibility  in  patients  with  tubercular 
infection  by  the  intracutaneous  method,  and  claim  that  the  result 
of  the  test  will  show  whether  the  case  in  point  is  one  of  tubercular 
infection  only  or  tubercular  disease.  We  cannot  share  this 
optimism  based  on  animal  experiment  on  account  of  our  own 
observations  in  tubercular  adults,  and  the  same  considerations 
which  show  Ellermann  and  Erlandsen's  quantitative  method  to 
be  unsuited  for  the  purpose.     Moller  shares  this  view. 

To  give  a  general  judgment  of  the  intracutaneous  test,  its 
advantages  must  be  weighed  against  its  drawbacks.  The  latter 
are  its  greater  technical  difficulty  and  the  discomfort  and  often 
pain  in  the  area  of  reaction  ;  the  former  chiefly  lie  in  the  fact 
that  it  is  superior  to  the  cutaneous  method  in  its  accuracy  in 
indicating  tuberculosis  and  is  applicable  to  cases  where  the  sub- 
cutaneous test  is  contra-indicated.  Its  sphere  -of  utility  seems  to 
be  limited  to  early  childhood.  In  adults  the  intracutaneous 
reaction  is  no  more  conclusive  than  the  cutaneous,  thereby  losing 
its  value. 

Veterinary  *n    vetermary   medicine   the   intracutaneous 

A       ....  reaction    has    proved    valuable.     Although 

Application.  .,  .  r  c    R 

rr^  there    is    at    present    no    prospect    of    the 


THE   SPECIFIC    DIAGNOSIS    OF   TUBERCULOSIS  57 

method  being  chosen  for  the  official  tuberculin  tests  on  cattle  at 
frontier  and  quarantine  stations,  yet  it  has  proved  itself  a  valuable 
aid  in  animal  experiments. 

'  Roemer  [75]  recommends  the  following  proceeding  in  veterinary 
practice  :  With  cattle,  shave  at  the  side  of  the  neck  a  square  surface  of 
about  10  cm.,  and  inject  into  the  skin  with  a  syringe  o"i  c.c.  of 
50  per  cent,  tuberculin,  the  dilution  being  made  with  normal  saline.  If 
the  reaction  is  positive,  a  considerable,  often  painful,  swelling  of  the  skin 
takes  place,  the  extent  of  which  may  be  exactly  estimated  after  forty-eight 
hours  with  the  help  of  calipers,  and  compared  with  the  thickness  of  the 
skin  ascertained  in  the  same  way  before  the  injection.  Differences  in  the 
thickness  of  the  skin  up  to  o'4  cm.  may  be  considered  as  negative,  o's  up  to 
o'7  cm.  as  doubtful,  and  swellings  of  more  than  0.7  cm.  as  distinctly 
positive  reactions,  provided  that  an  injection  of  50  c.mm.  tuberculin  in 
o'i  c.c.  fluid  is  given,  and  for  measurement  two  points  on  the  shaven 
surface  of  the  skin  exactly  5  cm.  apart  are  chosen  and  compressed  with 
the  fingers  for  the  adjustment  of  the  measuring  apparatus.  In  the  results, 
Roemer  found  complete  agreement  between  the  intracutaneous  and  sub- 
cutaneous reaction,  and  also  in  pigs  an  absolute,  and  in  cattle  an  almost 
invariable  agreement  between  the  result  of  the  reaction  and  the  condition  of 
the  animals  as  seen  after  slaughter. 

The  results  obtained  by  Martin,  R.  Kraus,  and  Zschokke  with  cattle 
and  pigs  were  almost  equally  favourable.  Zschokke  [76]  considers  it  to  be 
specially  important  from  the  point  of  view  of  the  veterinary  police  that 
a  subcutaneous  tuberculin  injection,  given  a  few  days  before,  exercises 
no  influence  upon  the  result  of  the  intracutaneous  reaction.  This 
might  otherwise  be  the  means  of  frustrating  the  result  of  quarantine 
inoculation  on  the  frontier.  Klimmer,  too,  considers  the  intracutaneous 
reaction  to  be  of  service  in  cattle ;  but,  according  to  his  experience,  the 
failures,  as  far  as  tubercular  animals  are  concerned,  amount  to  25  to  30 
per  cent. 

Without  doubt  the  intracutaneous  reaction  is  most  unequivocal  in  the 
case  of  tubercular  guinea-pigs.  Klimmer,  Kraus,  Roemer,  and  Joseph  are 
agreed  as  to  this.  Roemer  recommends  the  injection  of  guinea-pigs  with 
20  c.mm.  tuberculin  in  o'i  c.c.  fluid  in  the  middle  of  a  shaved  piece  of  skin. 
Then,  in  experiments  undertaken  with  Joseph,  he  observed  that  a  more 
severe  tubercular  infection  of  the  animal  corresponded  to  a  more  severe 
intracutaneous  tuberculin  susceptibility. 

The  extraordinarily  characteristic  intracu- 
sc  s  et  oa.  taneous  reaction  of  a  tubercular  guinea-pig 
has  been  used  by  Esch  [77]  for  the  rapid  detection  of  tubercle 
bacilli  by  animal  experiment.  The  material  to  be  examined  is 
injected  intraperitoneally  or  subcutaneously  into  two  guinea-pigs, 
and  after  the  ninth  day  following  the  injection  both  animals  are 
alternately  injected  every  third  day  with  tuberculin  intracutane- 
ously.  The  dose  used  is  20  c.mm.  in  o'i  c.c.  of  fluid.  If  the 
reaction  is  positive,  the  animal  is  killed  so  as  to  confirm  the 
biological  diagnosis  by  the  anatomical.     On  the  ground  of  his 


58  TUBERCULIN   IN   DIAGNOSIS   AND   TREATMENT 

comparative  experiments.  Esch  considers  this  by  far  the  most 
reliable  and  serviceable  method  of  obtaining  a  rapid  proof  of  the 
presence  of  tubercle  bacilli.  The  method  has  proved  useful  in  our 
own  experience  for  tubercle  bacilli  in  the  urine. 

Thus  the  intracutaneous  tuberculin  reaction  is  a  useful  means 
of  diagnosis  for  veterinary  purposes  and  of  considerable  assist- 
ance in  experimental  work  on  tubercular  animals.  Roemer  and 
Joseph  further  deduce  from  their  experimental  investigations  on 
animals  that  it  is  possible  to  ascertain  quantitatively  the  hyper- 
susceptibility  of  human  beings  infected  with  tuberculosis  and 
probably  possible  to  determine  successfully  whether,  in  individual 
cases,  tubercular  infection  or  disease  exists.  We  cannot,  how- 
ever, at  present  share  in  this  optimistic  belief ;  first,  because  of 
the  reasons  which  exist  for  not  using  the  intracutaneous  tuberculin 
test  on  man  and  also  because  of  the  same  considerations  which 
seem  to  show  that  the  graduated  cutaneous  test  of  Ellermann- 
Erlandsen  is  unsuitable. 


2.— THE  CONJUNCTIVAL  TUBERCULIN  TEST. 

The    discovery    of    the    conjunctival    tuberculin    test    stands 

historically  in  close  relation  with  v.  Pirquet's  cutaneous  reaction 

and  is  associated  with  the  names  of  Calmette  and  Wolff-Eisner. 

The  former  [78]  calls  it  the  "  ophthalmic  reaction,"  the  latter  [79] 

more    appropriately    the    "conjunctival    reaction,"    because    the 

normal  reaction  takes  place  exclusively  in  the  conjunctiva. 

0  r      In    the    technique    of    the    conjunctival    re- 

Preparation  of  .  ,         ,n.  r     .  ,  J  . 

_  ■  action,    the   choice   01    the   tuberculin    is  01 

Tuberculin  to  be  .   •  .  r^  1      ^  a 

great  importance.     Calmette  recommends  a 

^sec*-  tuberculin     precipitated    by    95     per    cent. 

alcohol,  the  Calmette  tuberculin  test,  made  from  bovine  tubercle 

bacilli  in  the  Pasteur  Institute  at  Lille. 

The  fluid  tuberculin  test  is  obtained  in  sealed  tubes;  an  ampulla 
available  for  2-3  tests  costs  is.  6d.,  six  ampullae  cost  7s.  6d.  The  dry- 
preparation  is  obtained  in  little  bottles  of  5  mg.,  price  3s.,  and  is  sufficient, 
with  the  addition  of  ten  drops  of  sterile  water,  for   10  reactions. 

Calmette,  with  an  experience  of  more  than  10,000  patients, 
characterizes  the  reaction  occurring  with  the  tuberculin  test 
(1  per  cent,  for  adults,  J  per  cent,  for  children)  as  without  danger. 

A  different  conclusion  was  arrived  at  by  Goerlich,  Siegrist, 
Wiens  and  Giinther,  Waldstein,  Schille,  Seligmann,  Stiilp, 
Schiele,  Barbier,  Cohn,  Klieneberger,  Trousseau,  v.  Szaboky, 
Mitulescu  and  other  writers,  at  home  and  abroad,   who  noticed 


THE   SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  59 

after  instillation  of  a  drop  of  \  or  i  per  cent,  of  Calmette's  tuber- 
culin test,  even  in  quite  healthy  eyes,  very  disagreeable  and 
often  permanent  injuries. 

A  preparation  similar  to  Calmette's  tuberculin  test  has  been 
put  on  the  market  by  the  Farbwerke  Hochst,  under  the  name  of 
"Tuberculosis  Diagnosticum  Hochst."  It  is  a  glycerin-free, 
dry  tuberculin,  obtained  from  Koch's  old  tuberculin. 

The    o'i    per    cent,     solution    of    the    Tuberculosis 

Tuberculosis  Diagnosticum  is  kept  ready  for  use  in  glass  tubes. 

Diagnosticum  Each  tube   contains   sufficient   for   at   least   one   re- 

l_...,.  action;   six  tubes  cost  4s.  6d.     The  preparation   in 

the   form  of  powder  in  tubes  containing  0*005   gr. 

costs  is.  6d.,  and  is  to  be  diluted  with  5  c.c.  of  cold  sterile  water  before  use. 

But  even  this  o'i  per  cent.  Tuberculosis  Diagnosticum 
Hochst  is  also  described  in  many  quarters  as  unreliable  and  very 
irritating.  Koch's  old  tuberculin  is  the  best  and  the  cheapest 
preparation  for  the  conjunctival  test. 

With    regard    to    the   concentration    of    the 

Concentration.  fluid  for  instilla.tion,  the  most  various  pro- 
positions have  been  made.  Our  experience  leads  us  to  recom- 
mend for  adults  a  i  to  4  per  cent.,  and  for  children  a  \  to  1  per 
cent,  dilution.  Stronger  concentrations  are  under  no  circum- 
stances to  be  employed,  whilst  weaker  ones  are  frequently  in- 
active. The  dilutions  can  be  made  by  oneself  (see  page  70),  with 
0*5  per  cent,  phenol  ;  they  should  be  kept  in  a  cool  place  and  in 
the  dark,  and  may  be  used  as  long  as  they  remain  absolutely 
clear. 

Our    attempts    to    replace    old    tuberculin    by    the 

Use    of  Other  albumose-free    preparation    were    not    satisfactory. 

Preoarations  ^or     veterinary     practice,     Klimmer     recommends 

phymatin  (Humann  and  Teisler-Dohna's  Chemical 
Works,  Dresden)  and  bovotuberculol  (Merck,  Darmstadt).  About  gg  per 
cent,  of  tubercular  cattle  reacted  to  phymatin  and  g3  per  cent,  to  bovo- 
tuberculol. 

M     ,      ,      .  The    technique     of    the    conjunctival     test 

consists  of  the  instillation  of  the  tuberculin 

Installation.  dilution    into    the    conjunctival    sac.  .  This 

must  not  be  done  till  one  is  certain  of  the  soundness  of  the  eye 
from  inquiry  and  careful  examination.  With  the  usual  drop- 
pipette  or  drop-bottle,  a  single  drop  must  be  introduced  into 
the  conjunctival  sac,  care  being  taken  that  the  drop  is  not 
immediately  shot  out  again.  In  doing  this,  the  pipette  must 
not  come  into  contact  with  the  eye.  On  the  other  hand,  care 
must  be  taken  that  the  drop  does  not  fall  from  too  great  a  height 


6o 


TUBERCULIN  IN  DIAGNOSIS  AND  TREATMENT 


on  the  conjunctiva  of  the  bulb,  or  even  on  the  cornea  itself,  and 
thus  give  rise  to  pain  and  contraction  of  the  lid  as  from  the 
presence  of  a  foreign  body.  The  consequence  would  be  either 
that  the  drop  would  be  entirely  shot  out  again  or  washed  away  by 
the  reflex  secretion  of  tears. 

The  instillation  is  most  successful  when  the  patient,  sitting 
on  a  chair,  inclines  the  head  somewhat  backwards.  The  operator, 
standing  a  little  to  the  side  and  in  front,  draws  down  the  lower 
lid,  lets  the  drop  fall  gently  into  the  conjunctival  sac,  as  near 
as  possible  to  the  inner  corner  of  the  eye,  and  holds  the  lid  for 
a  short  time  retracted,  so  that  the  conjunctiva  is  well  bathed  with 
the  solution.  Then  the  patient  is  allowed  to  remain  a  moment 
longer  with  the  eye  looking  up,  without  closing  it. 

Itching  now  and  then  occurs  after  the  instillation  and  may 


Repetition  of  the 
Instillation. 


give  rise  to  rubbing  of  the  eye,  unless  this  is  expressly  forbidden. 
A  bandage  to  protect  the  eye  is  unnecessary,  unless  there  is  any 
reason  to  suspect  malingering  and  an  intentional  simulation  of 
traumatic  irritation.  For  such  exceptional  cases  a  watch-glass 
bandage  is  to  be  recommended. 

The  disputed  question  must  be  considered 
whether     the     instillation     is     to     be     done 
once  or  repeatedly,   and  in   the   latter  case 
whether  in  the  same  or  the  other  eye. 

The  repetition  of  the  instillation  has  been  characterized  as 
incorrect  on  the  ground  that  the  introduction  of  tuberculin  into 
the  conjunctival  sac,  even  of  clinically  healthy  subjects,  gives  rise 
to  an  artificial  "  physiological  "  hypersusceptibility  of  the  con- 
junctiva, in  consequence  of  which  a  positive  reaction  occurs  on 
repetition.  Theoretically  this  is  possible;  in  practice  the  facts 
are  that  those  persons  who  give  a  conjunctival  reaction  on  repeti- 


THE   SPECIFIC    DIAGNOSIS    OF   TUBERCULOSIS  6l 

tion  of  the  instillation  may,  indeed,  be  clinically  healthy,  but  in 
point  of  fact  are  not  free  from  tuberculosis  and  are  really,  in 
confirmation  of  the  post-mortem  results  of  Naegeli,  Schmorl, 
Lubarsch,  Hamburger,  the  subjects  of  a  previous  infection  with 
tubercle,  whether  an  inactive,  obsolete  lesion,  or  one  merely 
quiescent.  Our  observations  [59]  agree  in  this,  that  persons 
really  free  from  tuberculosis — a  term,  it  may  be  observed,  not 
synonymous  with  "  clinically  healthy  "—give  no  conjunctival 
reaction,  even  when  the  instillation  is  repeated  with  4  per  cent, 
tuberculin  any  number  of  times  on  the  same  eye.  Tuberculin, 
even  when  repeatedly  instilled  in  the  conjunctiva,  cannot  produce 
susceptibility  in  an  organism  perfectly,  that  is  to  say,  anatomic- 
ally free  from  tuberculosis.  This  is,  moreover,  borne  out  by 
the  observation  that  the  vast  majority  of  new-born  babes  and 
infants  show  no  conjunctival  hypersusceptibility  in  spite  of 
repeated  instillations — they  are  really  free  from  tuberculosis. 
Our  experience  shows  that  in  adults  only  those  can  be  considered 
free  from  tuberculosis  who  do  not  react  to  four  graduated  instil- 
lations (1  to  4  per  cent.)  in  the  same  eye.  Re-instillation  is  in 
itself  not  incorrect,  but  repetition  in  the  same  eye  is  doubtless 
more  likely  to  reveal  inactive  and  obsolete  foci,  which  have  no 
practical  significance  for  the  physician. 

tu     d     t  Consideration    of    these   facts   suggests   the 

following  method  :    In  adults,  a  drop  of  a 
1  per  cent,  tuberculin  dilution  is  introduced 
into  the  conjunctival  sac,  and  if  the  result  is  negative  the  same 
process  is  repeated  two  days  later  on  the  other  eye  with  a  4  per 
cent  dilution.     In  children,  \  and  1  per  cent,  dilutions  are  used. 
Control   of  ^e    correct    control    and    interpretation    of 

the  reaction  is  most  important.  This  often 
begins  in  four  to  six  hours,  generally  in 
twelve  to  twenty-four,  reaches  its  acme  in  twenty-four  to  thirty- 
six  hours,  and  remains  visible  three  to  four  days,  in  exceptional 
cases  six  to  eight  days  and  even  longer.  Severe  reactions  occur, 
as  a  rule,  within  six  hours,  always  within  twenty-four  hours; 
slighter  ones  tend  to  appear  later  and  not  to  fade  so  soon  that 
they  are  not  apparent  after  eighteen  to  twenty-four  hours.  It 
follows  that  the  instillation  must  be  controlled  twelve  to  twenty- 
four  hours  after  it  has  been  made. 

n-~^      -ro       *■         Tne  positive  reaction  consists  in  an  inflam- 
urades  of  Reaction.         .  ,    ,,  . 

matory     reaction     of     the     conjunctiva,     of 

which,    with   Citron    [80],    we   can    distinguish    these    grades:  — 
Grade    1. — Reddening   of   the   caruncle  and   palpebral    con- 
junctiva. 


62  TUBERCULIN  IN  DIAGNOSIS  AND  TREATMENT 

Grade  2. — Intenser  reddening  with  involvement  of  the  ocular 
conjunctiva,  swelling  and  increased  secretion. 

Grade  3. — Intense  reddening  of  the  whole  conjunctiva, 
severe  chemosis,  much  fibrinous  and  purulent  secretion  and  small 
ecchymoses. 

A  moderate  reaction  is  shown  on  Plate   II. 

Observation  must  be  very  careful.  The  hyperemia  generally 
affects  first  and  in  characteristic  manner  the.  caruncle  and  semi- 
lunar fold.  Severe  reactions  are  easily  recognized  at  a  distance, 
moderate  ones  near  to ;  and  it  is  only  with  the  slight  reactive 
symptoms  that  it  is  necessary  to  get  the  patient  to  look  upwards 
and  outwards  successively  on  the  two  sides,  so  that  the  two 
caruncles  and  folds  may  be  accurately  compared.  In  every  case 
the  lower  lids  are  to  be  drawn  down  and  compared,  as  the  re- 
action may  be  limited  to  this  part  of  the  conjunctiva.  When 
severe  reactions  of  the  palpebral  conjunctiva  occur  the  follicles 
tend  to  stand  out  more  or  less  distinctly  as  glassy,  swollen  points. 
.  The  specific  nature  of  the  reaction,   which 

bpeci  icity.  only    occurs    in    the    organism    infected   by 

tuberculosis,  is  seen  to  be  highly  probable  from  bedside  and  post- 
mortem observations.  Specially  conclusive  are  the  experiences  of 
v.  Pirquet  and  Ganghofner  with  a  large  number  of  children,  the 
indications  given  by  the  cutaneous  test  being  confirmed  post 
mortem-.  Sorgo  has  objected  that  cutaneous  reactions  to  tuber- 
culin as  to  other  toxins— diphtheria,  dysentery,  cholera — are 
due  to  a  common  non-specific  cause — a  raised  susceptibility  of 
the  cutaneous  organs  of  tubercular  patients.  This  is,  however, 
refuted  by  the  very  careful  experiments  of  Zieler  [55]. 

The  conjunctival  reaction  is  a  specific  pro- 
Nature  of  the  Cess  dependent  on  the  hypersusceptibility 
Reaction ;  based  on  of  the  conjunctival  tissues  of  tubercular 
HvoersusceDtibilitv  individuals  to  tuberculin.  It  occurs  on  the 
basis  of  a  local  formation  of  antibodies,  and 
is  the  expression  of  a  local  tissue  reaction,  rendered  possible 
in  the  same  way  as  v.  Pirquet's  cutaneous  reaction,  by  the  fact 
that  the  conjunctival  tissue  of  tubercular  subjects  is  in  a  condition 
of  allergie  towards  tuberculin.  That  such  a  local  formation  of 
antibodies  as  a  fact  takes  place  has  been  proved  by  various 
authors  under  other  conditions.  Thus  Leber  has  given  a 
demonstration  of  specific  antibodies  in  the  aqueous  humour  in 
cases  of  ocular  tuberculosis. 

It   has    been  urged    against    the    specificity   of    the 

Specificity.  conjunctival  reaction  that  a  positive  reaction  may 

occur  also  in  the  non-tubercular,  in  diabetics,  in  the 


THE    SPECIFIC    DIAGNOSIS    OF   TUBERCULOSIS  03 

subjects  of  carcinoma,  in  the  manifest  stage  of  secondary  syphilis,  in  scar- 
latina, acute  rheumatism  of  the  joints,  enteritis,  arthritis  deformans,  and 
acute  bronchitis.  In  typhoid  patients  a  percentage  of  even  50  per  cent,  of 
positive  conjunctival  reactions  has  been  observed,  with  no  clinical  evidence 
of  concurrent  tubercular  disease.  From  this  the  conclusion  has  been  drawn 
of  increased  susceptibility  of  the  organism  to  bacterial  protoplasm  in 
general,  and  the  non-specificity  of  the  conjunctival  reaction  deduced. 

It  seems  to  us  that  in  all  these  cases  the  distinction  has  not  been  drawn 
sharply  enough  between  "  clinically  non-tubercular  "  and  "  free  from 
tubercle  in  an  anatomical  sense."  Macroscopical  examination  is  often  alone 
insufficient  to  settle  the  vexed  question,  since  tubercular  changes  may  only 
be  discovered  on  microscopical  examination,  or  even  only  by  animal 
experiment.  Such  confirmatory  proofs  are  lacking  in  the  observations  given 
above,  which  state  "  tuberculosis  not  -present  on  post-mortem  examination  " 
instead  of  "  tuberculosis  not  discovered." 

On  the  other  hand,  it  must  be  remembered  that  sensitive  eyes  which 
sometimes  respond  with  conjunctival  irritation  to  the  effect  of  draught, 
bright  sunshine,  terror,  &c,  also  react  conjunctivally  to  the  irritation  caused 
by  the  instillation  of  tuberculin  without  tubercular  conditions  being  present. 
Moreover,  now  and  then  special  conditions  may  be  present  in  the  eye,  which 
may  simulate  a  conjunctival  reaction  and  give  rise  to  a  false  diagnosis. 

In  very  cachectic  patients  and  cases  of  phthisis  just 
Non-OCCUrrence   of   before    death,    the    conjunctival    reaction  generally 

Reaction  ^a*ls    t0    aPPear-       Tllis    is'    however,    in    no    way 

evidence  against  its  specificity ;  rather  is  it  obvious 

that  in  such  individuals  the  ability  to  react  to  any  stimulus  whatever  cannot 

be  expected;  even  relatively  large  doses  of  tuberculin  given  subcutaneously 

are  inert. 


Drawback  to 


In  spite  of  its  specificity,   however,  a  great 
drawback    to    the    diagnostic    value    of    the 
ue  conjunctival  reaction  in  practice  lies  in  the 

of  Reaction.  fact   tnat   a    sjngie   instillation    is   quite   in- 

sufficient in  the  initial  stage  of  tuberculosis  in  which  diagnosis 
is  so  difficult ;  and  even  when  instillation  is  repeated  in  the  other 
eye,  the  reaction  only  occurs  in  about  half  the  cases  of  active  initial 
tuberculosis. 

It  is  evident  from  the  observations  of  Klimmer  and  Kiessig  [81]  on 
tubercular  cattle,  that  the  definiteness  and  certainty  of  the  conjunctival 
reaction  depend  on  the  concentration  of  the  tuberculin.  When  1  per  cent, 
dilutions  of  the  Hochst  tuberculin  were  used  no  reaction  took  place ;  5  and 
10  per  cent,  dilutions  did  not  always  produce  a  reaction,  and  then  merely 
a  very  slight  one,  only  just  perceptible.  Even  20  per  cent,  dilutions  did 
not  always  produce  a  reaction  in  tubercular  animals.  Reactions  were  only 
obtained  with  any  considerable  certainty  by  using  50  per  cent,  and  pure 
tuberculin. 


Unreliability  of 
the  Method. 


Thus  by  experiments  on  animals  our  asser- 
tion [59]  is  confirmed,  that  the  conjunctival 
tuberculin    test    is    unreliable    in    cases    of 


64  TUBERCULIN  IN  DIAGNOSIS  AND  TREATMENT 

human  phthisis,  since  the  reaction  may  be  negative  in  spite  of 
the  presence  of  active  tuberculosis,  just  because  10  per  cent,  tuber- 
culin and  still  stronger  concentrations  cannot  be  instilled  into  the 
eyes. 

There  is  yet  another  defect  in  the  diagnostic  value  of  the 
conjunctival  reaction.  From  the  positive  reaction  on  a  single 
instillation  the  conclusion  of  active  mischief  is  not  justified,  nor 
of  an  inactive  focus  from  the  positive  reaction  occurring  only  on 
repetition.  The  conjunctival  reaction  is  therefore  not  suited  for 
the  determination  of  the  activity  of  the  disease.  Moreover,  the 
instillation  of  stronger  or  weaker  concentrations  does  not  allow  of 
a  differentiation  :  a  case  of  active  tuberculosis  may  only  react  on 
the  second,  third,  or  fourth  instillation,  and  the  clinically  sound 
patient  with  inactive  tuberculosis  may  react  in  typical  manner  to 
the  first  instillation.  The  number  and  concentration  of  the  instil- 
lations necessary  to  call  forth  the  conjunctival  reaction,  therefore, 
do  not  give  even  an  approximate  indication  of  the  character  of  the 
tubercular  process. 

This  standpoint  is  also  supported  by  the  numerous  observations  made 
by  Klimmer  and  Kiessig  [81]  on  tubercular  cattle.  Using  5,  10,  and  20 
per  cent,  dilutions  of  Hochst  tuberculin,  no  special  relation  could  be 
shown  between  the  appearance  of  the  ophthalmic  reaction  and  the  extent, 
age,  and  nature  of  the  tubercular  process.  And  to  50  or  100  per  cent. 
Hochst  tuberculin,  as  a  rule,  all  tubercular  animals  reacted,  whether  the 
process  were  new  or  old,  limited  to  a  certain  locality,  or  widespread,  or 
generalized.  This  shows  that  the  conjunctival  reaction  is  not  suited  for 
discovering  the  activity  of  tuberculosis  among  cattle. 

r-,       .,  ■     l,  c     Harmful  action  of  the  conjunctival  test  in 

Possible  Harm  of    .  ,  ,      ,     ,  ,    , 

_         .  its  normal  course,  on  the  body  as  a  whole, 

the  Reaction.  ,  .,  ,    ,      ,.,      /  u  , 

and   on  the   general   health,    has   not  been 

observed,  nor  symptoms  of  general  reaction.  Subjective  discom- 
fort, such  as  photophobia,  itching,  burning  lachrymation,  as  the 
feeling  as  of  a  foreign  body  in  the  eye — the  last-named  due  to 
flakes  of  mucus — occurs,  as  a  rule,  only  with  the  severer  grades 
of  reaction,  and  soon  passes  off. 

But  there  are  already  recorded  indisputable  observations 
(Roemer,  Kalt,  Fehsenfeld,  Schrumpf,  and  others)  of  serious, 
persistent,  and  even  the  most  severe  disturbances  of  the  eye  in 
connection  with  the  reaction.  These  were  not  due  to  faulty 
technique  or  to  an  unsuitable  preparation,  but  solely  to  the  intro- 
duction of  1  per  cent,  old  tuberculin  into  the  conjunctival  sac, 
and  are  far  more  serious  than  a  doctor,  especially  in  private 
practice,  should  make  himself  responsible  for  (Wiens  and 
Giinther  [82]. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  65 

_  rIn  relation  to  harm  resulting  from  the  con- 

Two  Grades  of       ...   .  .   ..  ° 

junctival   inoculation  we  recognize  :  — 

Mischief  ^  'Yhe  severe  conjunctivitis  following  the 

Distinguished.        instillation,  with  its  highly  unpleasant  sub- 
jective symptoms. 

(2)  The  local  changes  attended  with  actual  danger  to  the 
eye.  In  order  to  avoid  the  former  as  far  as  possible  the  points 
already  mentioned  should  be  borne  in  mind,  especially  the  use 
only  of  an  absolutely  clear  old  tuberculin  dilution,  i  per  cent,  for 
adults  and  J  per  cent,  for  children  for  the  first  instillation;  for 
the  repetition  in  the  other  eye  4  per  cent,  and  1  per  cent,  dilutions 
respectively.  Further,  the  following  must  be  emphatically 
avoided  :  — 

(1)  A   second   instillation    in    the   same   eye 
Warnings.  after  positive   reaction,    no   matter  at   what 

interval. 

(2)  A  conjunctival  instillation  immediately  after  a  subcu- 
taneous tuberculin  test. 

(3)  A  subcutaneous  tuberculin  injection  after  a  conjunctival 
reaction  before  the  latter  has  completely  disappeared,  and  that  for 
several  days.  If  (1)  and  (2)  are  not  observed,  very  violent  con- 
junctival irritation  is  created ;  if  (3)  is  transgressed  a  recrudes- 
cence of  the  inflamed  conjunctiva  takes  place. 

n  .  The     recrudescence     of     the     conjunctival 

Recrudescence  .  .  ,  .    .      .  J       .    . 

.  reaction  after  subcutaneous  injection  of  the 

after  Subcutaneous  ,,     .     ,   „  r   +  1  r       •  1   •       1 

smallest    doses    of    tuberculin    is    explained 

Injection.  ^y  tjie  reactive  combination  of  the  remains 

of  the  tuberculin  left  behind  in  the  conjunctiva  with  the  anti- 
bodies newly  formed  by  the  subsequent  injection,  and  is  decidedly 
harmful  to  the  treatment.  M.  Wolff  [83]  first  drew  attention  to 
the  fact  that  there  are  cases — and  we  ourselves  have  observed 
several  of  them — in  which  the  conjunctival  reaction  recurs  after 
every  therapeutic  injection  of  tuberculin,  even  with  the  smallest 
dose,  sometimes  most  severely.  Therefore  we  have  repeatedly 
found  ourselves  obliged  to  cease  tuberculin  treatment  altogether. 
That  is  a  very  weak  point  in  the  conjunctival  method,  because 
after  establishing  the  diagnosis,  it  renders  the  most  efficient 
treatment,  that  with  tuberculin,  unavailable.  Wolff-Eisner  [84] 
indeed  looks  upon  this  recrudescence  of  the  conjunctival  reaction 
as  an  advantage  not  possessed  hitherto,  "  a  measure  for  the  doses 
to  be  used,"  which  are  excessive  when  the  reaction  reappears,  and 
considers  the  conjunctival  reaction  "  decidedly  advisable  as  a 
control  of  the  treatment."  We  cannot,  however,  accept  this 
attempt  to  turn  a  disadvantage  of  the  conjunctival  reaction  into 
an  advantage. 


66  TUBERCULIN   IN    DIAGNOSIS    AND    TREATMENT 

In  order,  as  far  as  possible,  to  avoid  accidents  which  mean 
actual  danger  to  the  eye,  every  instillation  must  be  preceded  by 
a  careful  inspection  of  both  eyes  and  inquiry  after  earlier  ocular 
disease.  But  we  must  distinguish  between  absolute  and  relative 
contra-indication. 

A1       .    .  Absolute    contra-indications    are    piven    by 

Absolute 
_  ....  ocular  disease,  no  matter  of  what  kind  and 

Contra-indications  ,    ,     ,  ,  •  ,    , 

in  what  stage,    even   processes  which   have 

in   bye  Diseases,     completely   run   their  course,    and   in   cases 

where  one  eye  is  sound  and  the  other  is  or  has  been  affected.     To 

this  category  belong  also  follicular  and  trachomatous  catarrh  of 

the  conjunctiva,  which,  according  to  Collin,  Wien,  and  Giinther, 

react   to   the   instillation   of   tuberculin    with   symptoms   of   equal 

irritation  and  an  abundant  production  of  new  follicles. 

.      .    r  ,       Absolute  contra-indication  is  also  given  bv 

In    Infants  and  ,.,..,,  ,      ,    " 

such  individuals  as  react  more  severely  than 

the   average,    infants   at   the   breast,    young 
Patients.  children  and  scrofulous  patients  of  all  ages. 

In  scrofulous  individuals  all  authors  concur  in  noting  the  occur- 
rence of  phlyctenules  and  similar  inflammatory  phenomena. 
Even  when  these,  as  is  the  rule,  pass  off  completely,  they  make 
medical  treatment  necessary,  and  may  lead,  without  proper  care, 
to  serious  and  permanent  affections  of  the  eye. 

Senility   must  also   be   looked   upon   as  an 
n  t>eni  i  y.  absolute     contra-indication,     for     then     the 

cornea  is  much  more  liable  to  injury  from  severe  reactions. 

Relative  Slight    chronic    hyperemia    which    so    fre- 

~  .     ..     x.  quently  occurs  and  severe  vascular  injection 

Contra-indications   nr    .    J        .  ,    .  .  ,  J    , 

of   the   conjunctiva   must   be   considered  as 

in  Slight  Affections  relative    contra-indications.       If    these    and 
of  the  Eye.  similar  conditions  of  the  eye  were  reckoned 

as  diseases,  there  would  be  so  few  healthy  eyes  remaining  as  to 
narrow  the  application  of  the  reaction  and  make  it  quite  insignifi- 
cant for  practice.  But  since  simple  and  slight  chronic  irritation  of 
the  conjunctiva  may  now  and  then  give  rise  to  severe  reactions, 
it  is  advisable  to  limit  the  diagnostic  instillation  in  these  patients 
as  far  as  possible.  This  limitation  is  also  advisable  on  the  ground 
that  chronic  irritative  conditions  easily  lead  to  misinterpretation 
of  the  result  of  the  reaction,  especially  as  there  is  an  element  of 
personal  equation  in  judging  a  slight  reaction. 

A  relative  contra-indication  applies  also  to 

In  Childhood.        childhood    in    general.       Various    authors 

found  in  children  such  severe  conjunctival  reactions  with  intense 

congestion,   inflammatory  oedema,   &c,   that  a  serious  condition 

arose.     The  instillation  is  also  not  easy  to  carry  out  in  trouble- 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  67 

some  children,  letting  alone  the  fact  that  the  dosage  is  very 
inexact  and  the  result  of  the  reaction  correspondingly  untrust- 
worthy when  the  instillation  only  imperfectly  succeeds,  or  when 
it  is  diluted  or  completely  washed  out  by  a  flow  of  tears.  There- 
fore with  children  we  make  our  diagnosis  by  safer  and  quicker 
methods. 

„       .,  ...  .        Finally,   the  use  of  the  conjunctival  test  is 

Possibility  ot        ..     .      , '        .  .,.,.,       r  1   -•  if 

.  r  limited  by  the  possibility  of  simulation.     It 

Simulation.  ig  pOSSjkle,  at  any  time  anc[  without  trouble, 

to  simulate  conjunctival  reaction  by  artificially  produced  irrita- 
tion, such  as  rubbing  the  inner  surface  of  the  lid  with  the  finger- 
nail or  a  match,  and  the  result  of  such  irritation  cannot  be  dis- 
tinguished in  any  way  from  a  genuine  normal  reaction.  This 
disadvantage  has  caused  the  medical  department  of  the  Prussian 
Ministry  of  War  to  reject  this  method  for  use  in  the  Service  by 
military  doctors. 

The    indications    for    the    conjunctival    test 
Indications.  w^j     ]3e     seen     to     ^e     very     limited;     we 

shall  refer  to  them  later  in  speaking  of  the  various  localizations 
of  tuberculosis.  Here  we  will  only  make  the  general  statement 
that  it  cannot  be  considered  anything  like  so  safe  a  diagnostic 
method  as  the  cutaneous  and  percutaneous  tests.  Although, 
thanks  to  the  greatest  caution  and  the  observation  of  numerous 
contra-indications,  we  have  not  as  yet  seen  lasting  injuries  to  the 
eyes,  we  do  not  consider  ourselves  justified  in  recommending  the 
general  use  of  the  conjunctival  reaction  in  medical  practice.  Over 
the  head  of  the  practitioner  hovers,  like  the  sword  of  Damocles, 
his  sense  of  responsibility,  and  in  this  case  more  especially,  for 
"  the  eye  is  the  light  of  the  body."  He  will  therefore  do  well,  as 
Schrumpf  [85]  suggests,  to  get  the  consent  of  the  patient  before 
proceeding  to  the  instillation  of  tuberculin,  pointing  out  the  possi- 
bility, even  though  it  may  not  be  very  probable,  of  injury  to  the 
eye.  We  should  certainly  anticipate  then  that  patients  would 
with  one  accord  decline  the  conjunctival  test. 

In  private  institutions  (clinics,  hospitals,  sanatoria)  it  will 
not  be  necessary  to  take  up  quite  this  point  of  view  as  regards 
the  conjunctival  reaction,  but  its  possible  dangers  must  always 
be  borne  in  mind,  and  in  consequence  it  must  only  be  used  with 
special  caution  and  careful  selection  when  certain  indications  are- 
present.  In  public  institutes,  too,  the  conjunctival  tuberculin  test 
should  not  be  used  under  any  circumstances  merelv  for  the  purpose 
of  scientific  research. 

No  Value  in  ^e  conilinctlva^  reaction  has,  according  to 

.  our  experience,  no  value  in  prognosis.    We 

°n      '  '  are  not  dissuaded  from  this  opinion  by  the 


68  TUBERCULIN   IN   DIAGNOSIS    AND   TREATMENT 

publications    of    Meissen,    Schuster,    and    Baer,    who    take    their 

material   from   one   institution   alone   and   differ   widely    in    their 

arguments  without  proving  the  prognostic  value  of  the  reaction. 

What  prognostic  help  can  be  afforded  by  a  test  which  gives  a 

faulty  diagnostic  result  in  50  per  cent,  of  cases  ?     That  it  is  as 

good  as  no  help  at  all  was  emphasized  at  the  annual  meeting  of 

the   British    Medical   Association   in    Belfast   (1910)   by   Calmette 

himself,  who  has  command  of  a  very  large  material  and  would  be 

the  last  to  lower  the  value  of  his  ophthalmic  reaction. 

_  ,    ,     ,  L  The  general   judgment  of  the  conjunctival 

General  Judgment   .  ,     J     °  .       .      .  .  ,,J  . 

0  test    mav    be    summarized    as    follows :     A 

negative  result  does  not  prove  the  absence 

Conjunctival  Test.   Qf   act[ve   tuberculosis.        A   positive   result 

only  proves  the  presence  of  a  tubercular  focus  in  the  body  of  the 

patient  without  giving  information  as  to  its  activity  or  inactivity. 

We  must  expressly  warn  physicians  against  regarding  the 
■once  repeated  instillation  as  sufficient  and  its  negative  result  as 
identical  with  "  tubercle-free  "  or  "  inactive  tubercle  not  demand- 
ing treatment  at  the  time."  Wolff-Eisner's  [84]  assertion  that  the 
•conjunctival  reaction,  in  contra-distinction  to  all  other  tuberculin 
tests,  is  the  reaction  of  active  tuberculosis  has  been  and  still 
remains  refuted.  And  it  would  be  a  fatal  backward  step  in 
diagnosis  if  Wolff-Eisner's  estimate  of  the  test  were  to  be 
regarded  as  adequate  even  if  only  by  a  limited  number  of 
physicians. 

In  addition  to  its  uncertainty,  there  is  the  possibility  of  serious 
harm.  This  renders  the  test  unsuitable  for  general  practice,  or 
■only  admissible  with  certain  reservations.  In  private  institutions, 
too,  it  should  only  be  employed  with  observation  of  definite 
absolute  and  relative  contra-indications.  As  a  rule  the  con- 
junctival test  is  only  indicated  when  a  therapeutic  measure  is 
dependent  on  its  result,  and  definite  reasons  justify  its  preference 
to  other  diagnostic  methods. 

_,_   .  ..  Wolff-Eisner  has  recommended  as  a  "  modi- 

Tuberculin  r        •  r    ,  •  -1  •  .» 

fication  of  the  conjunctival  test  in  practice 
Vaseline.  the   use  of  tuberculin   vaSeline.     "With  a 

sterilized  glass  tube  a  quantity  of  tuberculin  ointment  the  size  of 
a  pea  is  introduced  into  the  conjunctival  sac,  rubbing  the  oint- 
ment into  the  lower  lid,  which  is  drawn  down,  keeping  the  lids 
apart  for  about  a  minute  by  pulling  down  the  lower  lrd  with  the 
finger."  The  reactions  thus  attained  are  said  to  be  similar  in 
appearance  and  course  to  the  conjunctival  reactions  produced  by 
liquid  dilutions.  The  exceptional  durability  of  the  preparation  is 
mentioned  as  a  special  advantage. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  69 

By  this  modification  the  conjunctival  test  is  not  freed  from 
the  odium  resting  upon  it — in  essentials  it  remains  the  same. 
Besides,  it  is  unintelligible  that  Wolff-Eisner  should,  on  the  one 
hand,  reject  a  dilution  of  tuberculin  kept  for  eight  days  as  too 
old  and  dangerous,  and,  on  the  other  hand,  declare  that  a  tuber- 
culin ointment  has  exceptional  keeping  powers,  and  is  effective. 
In  our  opinion  a  \  per  cent,  watery  solution  of  carbolic  acid  is  a 
much  more  reliable  vehicle  for  tuberculin  than  vaseline. 

After  the  failure  of  the  tuberculin  instillation  it  is  not  likely 
that  a  practitioner  would  be  enticed  into  rubbing  tuberculin  oint- 
ment into  the  eyes  of  his  patients.  Nevertheless,  we  feel  it  our 
duty  most  expressly  to  warn  all  doctors  against  such  a  diagnostic 
manipulation.  That  "  tuberculin  vaseline  "  is  more  dangerous 
and  unsuitable  for  the  human  eye  than. the  instillation  of  tuber- 
culin is  evident,  the  method  is  more  troublesome,  the  dosage — a 
quantity  the  size  of  a  pea — quite  inexact  and  control  as  to  whether 
the  ointment  is  good  or  not  quite  impossible.  The  conjunctival 
test  "modified  for  practice"  by  means  of  tuberculin  vaseline 
should  be  decisively  rejected. 

|v.         I  Lafite-Dupont  and  Molinier  have  recommended  the 

Nasal  Reaction  (Rhino-reaction)  as  a  substitute  for 
Reaction.  t]ie  ophthalmo  reaction,  as  it  is  free  from  risk  and 

not  visible  externally.  A  swab  of  cotton-wool  the  size  of  a  small  lentil  is 
dipped  into  a  1  per  cent,  dilution  of  Calmette's  tuberculin  and  applied  for 
ten  minutes  to  the  lower  turbinal  or  the  septum.  After  twelve  to  eighteen 
hours  the  reaction  occurs,  consisting  of  congestion  and  exudation  of  the 
part  dabbed,  and  leads  to  the  formation  of  a  slightly  bleeding  scab,  which 
lasts  from  four  to  eight  days,  and  after  peeling  off  leaves  behind  a  slightly 
inflamed  spot.  There  seems  to  be  as  little  need  for  the  Nasal  Test  as  for 
the  urethral,  rectal,  and  vaginal  tuberculin  tests.  The  last-named  is 
possibly  of  value  in  veterinary  medicine;  Richter  recommends  it  for 
cattle. 

3.— THE   SUBCUTANEOUS  TUBERCULIN   TEST. 

The  technique  of  the  subcutaneous  reaction 
Selection  of         is  of  the  greatest  importance  if  its  full  value 
Tuberculin  to  be    is    to    be    obtained    and    its    disadvantages 
Employed.  excluded.     It  will  therefore  be  described  in 

detail. 
As  a  rule,  only  Koch's  tuberculin  (old  tuberculin)  is  em- 
ployed. For  two  years  we  have  preferred  Koch's  albumose-free 
tuberculin,  which,  owing  to  the  removal  of  the  simultaneous  toxic 
effect  of  the  albumose,  usually  renders  the  general  reactions  much 
milder. 


70  TUBERCULIN    IN    DIAGNOSIS    AND  "TREATMENT 

The  bovine  old  tuberculin  is  less  suitable  for  the  purpose,  Marmorek's 
serum  and  C.  Spengler's  IK  quite  unsuitable.  The  action  of  Rosenbach's 
and    other    tuberculins    has    not    yet    been    sufficiently    investigated. 

_.  .       The  tuberculin  must  be  diluted,  and  this  is 

Preparation  of        ,  .,,    ,  ,         .    '        .  , 

done  with  f  per  cent,  phenol  solution  and 

Dilutions.  the  dilutions  kept  m  test-tubes  which  have 

been  sterilized  by  boiling  or  passing  through  a  flame,  and  closed 

with  a  cotton-wool  plug,  or  in  small  sterilized  bottles  (10  c.c.  in 

capacity)  with  wide  necks  and  glass  stoppers. 

Besides  the  tuberculin  itself,  the  \  per  cent,  phenol  solution 

and   the   sterile   test-tubes,    only   two   pipettes   of    i    and    10   c.c. 

capacity  accurately  graduated  into  tenths  or  an  accurate  syringe 

are  required  to  obtain  accurate  results. 

-    .,        ,  Only    two    dilutions    are    required    for    dia- 

Authors  ' . 

gnosis  :  A  i  per  cent,  and  a  i  per  thousand. 

Method.  W  *.     a-\  *•  a   u 

Ihe    i    per   cent,    dilution    is   prepared   by 

taking  one  division  of  the  small  pipette  (=o"i)  from  the  stock 

solution  and  0/9  c.c.  of  J  per  cent,  phenol  with  the  large  pipette, 

and  mixing  them  in  a  test-tube.     This  dilution  contains  in  10  c.c. 

100  c.mm.  of  tuberculin  ;  in  a  1  c.c.  syringe  10  c.mm. ;;  and  in 

one  division  of  the  syringe  1  c.mm.  of  tuberculin.     It  should  be 

labelled  :  — 

No.  I.     (Dilution  r  :  ioo) 

1  division  =  i*o  c.mm.  tuberculin. 

From  this  1  per  cent,  solution  the  other  (or  1  per  1,000)  is 
obtained  by  taking  the  small  pipetteful  of  it  and  mixing  in 
another  test-tube  with  9  c.c.  J  per  cent,  phenol.  This  contains 
in  10  c.c.  10  c.mm.  of  tuberculin;  in  a  syringeful  1  c.mm.;  and  in 
one  division  of  the  syringe  o"i  c.mm.  of  tuberculin.  It  should 
be  labelled  :  — 

No.  2.     (Dilution  1  :  i,coc) 

1  division  =  o- 1  c.mm.  tuberculin. 

In  actual  practice  the  procedure  is  as  follows  :  Two  sterilized 
test-tubes  are  labelled  as  above,  and  in  No.  1  is  placed  9*9  c.c, 
in  No.  2,  9  c.c.  of  J  per  cent,  phenol  with  the  larger  pipette.  With 
the  smaller  pipette  o'l  c.c.  tuberculin  is  taken  from  the  stock 
bottle  and  mixed  in  No.  1  ;  from  this  mixture  1  c.c.  is  taken  with 
the  same  pipette  and  mixed  in  No.  2 — the  whole  a  work  of  a  few 
moments. 

According  to  the  nomenclature  in  grammes  and  milli- 
grammes formerly  used,  one  division  of  No.  1  dilution  (=  1  c.mm.) 
contains  1  mg.  and  one  division  of  No.  2  dilution  (=o'i  c.mm.) 
a  tenth  of  a  milligramme  of  tuberculin. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  7 1 

~...    ..  ...     ..        Dilutions  may  easily  be  prepared  with  the 

Dilution   with   the         .  ..  J.  ;.TT     L      ;        ,      T  .  , 

tuberculin  svnnge.     We  preter  the  Lieberg 

Svrinffe  •  • 

y       6   "  tuberculin     syringe    with     platinum-iridium 

needle,'  very   accurately   graduated,    holding    i    c.c.    and    with    a 

narrow   lumen,    so  that  the  divisions  be  far  apart.     It   is   made 

entirely  of  glass,  and,  once  sterilized  and  kept  in  carbolized  water, 

it  remains  sterile,  whilst  the  needle  can  be  sterilized  in  a  moment 

by  heating  in  the  flame. 


The  procedure  is  then  as  follows:  One  division  (o'l  c.c.)  of 
tuberculin  is  drawn  up  into  the  syringe  and  then  nine  divisions 
of  diluting  fluid  (J  per  cent,  carbolized  water).  The  contents  of 
the  syringe  are  mixed  by  drawing  the  piston  in  and  out  and 
shaking.  This  gives  Dilution  i,  one  division  of  which  contains 
10  c.mm.  (10  mg.)  of  tuberculin. 

If  Dilution  2  is  required,  one  division  of  Dilution  i  is  re- 
tained in  the  syringe  and  nine  divisions  of  carbolized  water 
drawn  up.  The  contents  of  the  syringe  are  mixed;  Dilution  2 
is  obtained,  each  division  of  which  contains  i'o  c.mm.  (1  mg.) 
of  tuberculin. 

Dilution  3  is  obtained  from  Dilution  2  by  retaining  one 
division  in  the  syringe  and  drawing  up  nine  divisions  of  the 
diluting  fluid,  and  the  contents  are  mixed  as  before.  One  divi- 
sion of  Dilution  3  contains  o"i  c.mm.  (1/10  mg.)  of  tuberculin. 
Thus  any  required  diagnostic  dose  can  be  obtained  direct  from 
the  syringe  or  placed  in  one  of  the  small  bottles  or  tubes  and 
kept  for  future  use. 

When  the  dilutions  are  prepared  according  to  the  directions 
and  placed  in  the  dark  in  a  cool  place,  they  can  be  kept  for 
several  weeks.  As  a  general  rule,  they  can  be  used  as  long  as 
they  remain  perfectly  clear.  Turbid  solutions  must  always  be 
discarded. 

It  is  not  advisable  to  have  the  tuberculin  dilutions  made  up 
from  prescription  by  the  chemist  on  account  of  the  high  price 
charged.  Besides,  sterilized  dilutions  of  old  tuberculin  are 
obtainable  ready  for  use  in  hermetically  closed  glass  tubes ;  the 
top  of  the  capsule  is  broken  off,  the  contents  drawn  up  into  the 
syringe  and  injected.  It  is  well  for  those  physicians  who  do 
not  regularly  employ  diagnostic  tuberculin  to  get  the  local  chemist 
to  keep  in  stock  the  sterilized  injection  doses  which  are  required 
for  diagnosis  (o'2 — i'o — 5 — 10  c.mm.).     It  must  be  remembered, 


72  TUBERCULIN    IN    DIAGNOSIS    AND   TREATMENT 

however,  that  these  dilutions  become  less  active  in  course  of  time. 

The  date  of  preparation  should  therefore  be  placed  on  the  tube. 

The    subcutaneous    injection    of    tuberculin    prescribed    by 

Koch   has   the   advantage   of   the    most   exact    dosage,    which    is 

necessary    for    tuberculin — the    most   potent    drug    in    the    whole 

Pharmacopoeia  for  diagnosis. 

..    ..      .      .  In    addition    to    the    subcutaneous    method, 

Method  of  ,r      ,  .,  ,     , 

Mendel  s    intravenous    method    comes    into 

Administration.  questjon>  Tn  the  action  of  tuberculin  given 
by  these  two  methods  there  is  only  a  difference  of  time  and 
degree ;  the  reaction  occurs  much  sooner  and  is  far  more  marked 
by  the  intravenous  method.  But  this  is  no  advantage;  on  the 
contrary,  the  subcutaneous  test  is  easier  to  perform  and  applicable 
to  every  case,  e.g.,  children  and  women  with  arm-veins  difficult 
to  make  prominent.  So  what  Koch  [86]  stated  in  his  first  pub- 
lication, still  holds  to-day.:  "To  obtain  a  reliable  result,  it 
(tuberculin)  must  be  given  subcutaneously." 

The  injection  is  made  under  the  skin,  which 
Technique  of        should  be   rubbed    with    ether.     The   rapid 
Administration.       insertion  of  the  sharp  needle  is  then  almost 
painless. 

_  The    best    site    for    injection    is    the    back, 

Site 

below  the  level  of  shoulder-blades  on  a  level 

with  the  last  ribs  and  alternately  on  the  two  sides.  In  spite  of 
aseptic  precautions,  it  sometimes  happens,  especially  if  the  re- 
action be  severe,  that  there  is  a  painful  infiltration  of  the  needle 
track,  the  so-called  needle  track  reaction,  which  will  be  described 
later. 

The  arm  is  still  often  chosen  as  the  site  for  injection.  This  may  be 
more  convenient,  because  the  patient  does  not  need  to  undress.  Yet  injec- 
tions in  the  upper  or  lower  arm  are  not  to  be  recommended.  They  often 
result  in  very  severe  needle-track  reactions,  not  infrequently  in  extensive 
infiltration,  which  hampers  the  free  movements  of  the  arm  in  a  disagree- 
able manner.  This  may  occur  when  no  error  in  technique  has  been  made 
or  aseptic  precautions  overlooked.  According  to  Schiitz  and  Videky  the 
local  inflammatory  irritability  of  the  skin  and  of  the  subcutaneous  connec- 
tive tissue  is  greatest  in  the  arm. 

The  best  time  for  the  injection  is  the  early 
hours  of  the  forenoon.  It  is  not  advisable 
to  inject  in  the  evening,  because  reactions  mav  set  in  after  six 
hours,  pass  unnoticed  during  sleep  and  have  completely  passed 
away  by  the  following  morning,  with  the  result  that  the  reaction 
escapes  the  notice  of  the  physician  also  and  the  next  dose  is  un- 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  73 

necessary  or  too  large.  According  to  Hollmann  [87],  the  tuber- 
culin reaction  commences  four  to  eight  hours  sooner  with  morning 
injections  than  with  evening;  it  almost  always  occurs  during 
the  day,  a  result  of  the  action  of  light  and  of  the  increased 
metabolism  by  day. 

Without  exception  an  interval  of  at  least  forty-eight  hours 
must  be  left  between  successive  injections,  as  even  considerable 
febrile  reaction  may  set  in  after  thirty  hours. 

„  r  Before  a  diagnostic  injection  the  range  of 

Range  of  ,  ,  ,    /  °    , 

the   patient  s   normal   temperature   must  be 

Temperature  sufficiently  known.  For  this  purpose,  two- 
Ad  missible.  or  three-hourly  observations  of  the  tem- 
perature should  be  taken  in  the  mouth — under  the  tongue,  keep- 
ing the  mouth  carefullv  shut,  for  ten  minutes — for  at  least  three 
days  in  the  case  of  patients  with  apparently  normal  temperature. 
The  technique  must  be  carefullv  explained  to  the  patient  and  the 
temperature  taken  on  the  first  occasion  in  the  presence  of  the 
physician  or  the  nurse;  afterwards  it  can  be  taken  by  the  patient 
himself  with  sufficient  exactitude. 

The  maximum  temperature  at  which  a  diagnostic  injection 
can  still  be  made  was  fixed  by  Koch  at  370  C.  He  says  :  "  The 
temperature  should  during  a  whole  day,  or  better  during  two 
days,  not  range  above  370  C."  This  limit  should  be  retained  with 
axillary  temperature  measurement,  which  we  do  not  recommend 
on  account  of  its  uncertainty.  With  mouth  temperature  the 
upper  limit  may  generally  be  put  at  37'2°  to  37*3°  C.  Patients 
with  higher  temperature  must  remain  in  bed  until  it  has  fallen 
to  this  limit,  and  after  getting  up  it  must  still  remain  normal. 

If  the  temperature  has  been  artificially  brought  down  to 
normal  by  antipyretic  drugs,  then  the  injection  must  not  be 
made  until  the  temperature  has  been  quite  normal  for  clays  with- 
out their  use. 

The  best  times  for  the  three-hourly  measurements  are  8  and 
11  a.m.,  and  2,  5,  and  8  p.m.,  and  it  is  important  that  the  same 
times  should  be  taken  for  the  readings  after  injection,  so  that  anv 
variations  which  occur  may  be  correctly  interpreted.  It  is  fur- 
ther advisable  to  instruct  the  patient  to  take  his  temperature  at 
any  other  time  that  he  mav  feel  at  all  out  of  sorts;  if  necessary, 
at  night.     Four-hourly  readings  are  insufficient. 

In  the  female  the  time  of  the  injection  should  not  be  so 
chosen  that  the  reaction  could  be  disturbed  by  the  occurrence 
of  premenstrual  or  menstrual  fevers ;  and  also,  out  of  considera- 
tion for  the  patient's  general  health,  these  times  should  not  be 
chosen  for  purposes  of  diagnosis. 


74  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

The  dosage  of  tuberculin  given  subcutaneously  is  different 
for  adults  and  for  children.  We  will  first  discuss  the  deter- 
mining factors  in  adults. 

With  regard  to  the  size  of  the  dose  to  begin 
Dosage.  ancj  encj  wjtT^    there   is  as  yet   no   general 

consensus  of  opinion.  In  the  course  of  years  a  surprising  number 
of  methods  have  been  evolved  by  different  authors  out  of  different 
clinical  material,  all  having  the  same  end  in  view — to  choose 
doses  large  enough,  but  not  too  large.  Koch's  first  instruction 
[86],  which  Beck  [88]  worked  out  on  more  than  2,500  cases, 
ran  as  follows  :  Begin  with  1  c.mm.  (1  mg.)  tuberculin,  increased 
to  5  and  finallv  10  c.mm.  Later  [89]  he  modified  this  procedure 
slightlv  and  made  it  more  precise  :  With  weakly  subjects  begin 
with  o'l  c.mm.;  with  strong  subjects,  in  whom  only  slight  tuber- 
cular lesions  are  suspected,  begin  with  1  c.mm.,  increased  to 
5  c.mm.,  and  then  to  10  c.mm.,   repeated  if  necessary. 

With    regard   to   the    initial    dose,    opinion 
initial   Dose.  -g   nQW  practiCallv  unanimous.     A  dose  of 

ro  c.mm.  (1  mg.)  is  unnecessarily  large;  smaller  doses  are 
sufficient,  especiallv  in  the  case  of  weakly  or  nervous  individuals 
and  in  cases  where  a  fresh  infection  is  suspected,  when  a  severe 
reaction  is  likely  to  occur.  Too  small  a  dose  is,  however,  equally 
undesirable  for  physician  and  patient,  as  it  only  delays  the 
decision.  We  recommend  that  the  initial  dose  should  be  fixed 
at  o'2  c.mm.  of  tuberculin  (2/10  mg.).     (See  Chart  Xo.  1.) 

.  r  Ldwenstein  and  Kauffmann  [go]  proposed, 

Increase  of  .  r  Ly  J .       *\ 

in  the  case  of  patients  who  are  going  about, 

Qncp  p 

not  to  increase  the  dose  at  all,  but  to  repeat 
the  same  small  dose  of  o'2  c.mm.  four  times  within  ten  to  twelve 
days,  and  so  force  a  specific  reaction  ;  a  proposal  with  much  to 
recommend  it. 

The  same  standpoint  was  taken  bv  Pickert,  who  limited 
himself  to  the  repetition  of  small  doses.  There  is  the  less  need 
to  discuss  the  theoretical  basis  of  these  proposals,  as  our  own 
experiments — carried  out  independentlv  of  each  other — -have 
shown  that  neither  of  these  methods  gives  reliable  results.  It  is 
not  the  frequent  repetition  of  the  same  small  dose  that  is  of 
decisive  importance  for  the  occurrence  of  reaction,  but  the  size 
thereof,  the  actual  quantity  of  tuberculin.  The  great  majority  of 
observers  take  the  view  that  the  difference  between  the  increasing 
doses  must  not  be  too  small,  or  a  gradual  tuberculin  tolerance 
occurs  even  in  the  tubercular  subject  and  leads  to  the  non- 
appearance of  reactions  in  spite  of  existing  tuberculosis.  This  is 
illustrated  with  all  clearness  by  the  gradual  process  of  tuberculin 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  75 

treatment  on  the  lines  of  Goetsch.  For  the  production  of  re- 
actions a  sudden  increase  of  dose  is  an  absolute  essential.  On 
the  other  hand,  too  great  differences  between  successive  doses 
are  not  to  be  made,  on  account  of  the  risk  of  severe  reactions. 
The  sequence  of  dosage  recommended  is  then  as  follows  :  Increase 
from  o'2  c.mm.  to  i  c.mm.  for  the  second  dose,  to  5  c.mm.  for 
the  third,  and  finally  to  10  c.mm.  for  the  fourth  and  last.  (See 
Charts  2,  3  and  4.) 

„  ,      This  method  is  also  in  accordance  with  the 

Phenomenon   ot  ,      .        it_       r  .    .     ,.  m     .   u 

general   view   that   tour    injections   must    be 

Anaphylaxis.         made   before   the   presence   of   a   tubercular 

process  can  be  excluded.     But  against  this  repetition  an  argument 

has  quite  recently  been  raised  on  the  ground  of  the  phenomenon 

of  anaphylaxis,   that  the   repetition    is   itself  a  source  of  error. 

Applied  to  the  conditions  of  tuberculin  diagnosis  anaphylaxis  might  be 
caused  by  assimilation  of  the  proteins  contained  in  the  tuberculin,  and  on 
repetition  of  the  injection  might  produce  the  appearance  of  reactionary 
symptoms  without  tubercular  infection  being  present.  Theoretically  that 
may  be  possible,  but  in  practice  the  quantity  of  the  foreign  albuminous 
substances  injected  into  the  body  is  so  small  that  the  production  of  hyper- 
susceptibility  is  quite  improbable. 

Then  the  hypersusceptibility  towards  the  toxins  of  tuberculin  would 
come  into  question  in  the  sense  that  in  healthy  persons  the  toxins  injected 
in  the  tuberculin  create  an  anaphylaxis  in  consequence  of  which  the  second 
injection  becomes  positive.  This  is  contradicted  by  the  daily  observation 
that  the  phenomenon  of  anaphylaxis  fails  to  appear,  in  spite  of  repetition 
and  increase  of  the  dose  of  tuberculin,  in  the  healthy,  in  a  certain  number 
of  suspected  cases,  in  non-tubercular  pulmonary  disease,  and  in  earliest 
childhood  (when  other  forms  of  reaction  are  easily  produced) — clearly 
because  in  these  cases  there  are  no  tubercular  forms  in  the  organism. 

Finally  the  specific  toxic  hypersusceptibility  of  Wolff-Eisner  is  brought 
into  the  field  against  the  repetition  of  the  diagnostic  injection  of  tuberculin. 
He  says  that  the  repetition  of  the  subcutaneous  injection  which  is  in  general 
use  for  the  diagnosis  of  active  tuberculosis  is  of  no  assistance.  For  the 
"  stimulus  "  caused  by  the  first  injection  is  sufficient  in  cases  of  inactive 
tuberculosis  also  to  cause  a  reaction  on  the  repetition  of  the  injection  which 
cannot  in  any  way  be  distinguished  from  that  of  the  case  of  active  tuber- 
culosis. Those  who  wish  to  use  the  subcutaneous  tuberculin  test  must  make 
the  dose  of  such  a  size  that  the  first  injection  is  followed  by  a  reaction. 
The  absolute  impracticability  of  this  proposal  is  evident.  But  apart  from 
this,  this  purely  speculative  conception  is  contradicted  by  the  practical 
results  of  nearly  twenty  years ;  in  thousands  of  cases  it  has  been  proved 
that  undoubted  cases  of  tuberculosis  in  all  stages  do  not  react  on  the  first 
injection  of  tuberculin,  but  do  react  on  the  second,  or  even  perhaps  not 
until  the  third  or  fourth  dose. 

We  must  therefore  regard  the  attempt  to  discredit  the  tuber- 
culin  injection  test  (which   has  been  proved  successful  a  hundred 


76  TUBERCULIN   IN    DIAGNOSIS    AND    TREATMENT 

thousand  times)  by  the  suggestion  of  anaphylaxis  as  being  en- 
tirely misguided.  The  repetition  and  increase  of  dose  for 
diagnosis  is  correct  and  necessary. 

_.  J..  In  this  connection  it  must  be  carefully  borne 

Precautions         .         •     ,    ,         ,      r  n  i  i 

in  mind  that  the  following  dose  may  only 

in  net  easing  ^  rajsecj  when  the  previous  one  has  pro- 
pose, duced  no  rise  of  temperature.  If  the  tem- 
perature has  clearly  risen,  even  by  a  few  tenths  of  a  degree,  the 
dose  must  not  be  increased,  but  the  same  one  repeated  after  the 
temperature  has  fallen  quite  to  normal.     (See  Charts  5  and  6.) 

The  maxim  to  increase  the  dose  onlv  when  the  preceding 
one  has  been  altogether  without  reaction  is  of  importance  in 
more  than  one  direction.  Firstly,  it  protects  from  the  "  tuber- 
culin danger,"  which,  if  it  occur  now  at  all,  is  only  observed  by 
those  who  do  not  adhere  to  this  simple  and  easily  carried  out 
rule.  Secondly,  the  increasingly  severe  reaction  after  the 
repetition  of  the  same  dose  is,  according  to  Koch  [86],  "  a 
phenomenon  specially  characteristic  of  the  action  of  tuberculin, 
and  mav  be  regarded  as  an  infallible  indication  of  the  presence 
of  tuberculosis."  Finally,  in  doubtful  cases  it  may  be  taken 
as  characteristic  of  a  negative  result  when  a  slight  rise  of  tem- 
perature disappears  or  is  less  marked  after  repetition  of  the  same 
dose,  and  still  more  so  after  the  next  larger  one. 

It  may  then  be  taken  as  an  axiom  :  Only  increase  the  dose 
when  the  preceding  injection  has  been  borne  without  reaction; 
otherwise  repeat  the  same  dose. 

The   acutest    discussion    centres    round   the 

Maximal   Dose.  „•         r  +1  ■       1    1  •        +u     a~  ^ 

question  of  the  maximal  dose,  i.e.,  the  dose 

which,    if  borne  without   reaction,    demonstrates   the   absence   of 

tuberculosis. 

Koch  [89],  fixed  the  limiting  dose  at  10  c.mm.,   which,   for 

greater  certainty,  he  was  in  the  habit  of  giving  twice;  when  no 

reaction  results  he  held  himself  justified  in  assuming  that  "  no 

recent  or  progressive  tubercle  "  was  present.     On  the  ground  of 

some   hundreds   of   observations,    we   are   content   with   a   single 

maximal  dose  of  10  c.mm.,  others  with  one  of  6  or  of  5  c.mm., 

and  even  this  is  held  by  some  to  be  too  large.     We  cannot,  then, 

yet  speak  of  a  generally  accepted  limiting  dose  with  which  the 

tubercular   subject   must    react   and   the   non-tubercular   can    not. 

It   is   more   than    doubtful   whether   such   a   limit    could   ever   be 

determined  with  mathematical  exactness.     The  occurrence  of  the 

tuberculin  reaction  as  a  biological  phenomenon  depends  on  the 

ability  of  the  organism  to  react,   and  this  again   on   the  general 

constitution  and  on  the  local  conditions  for  reaction  present  at 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  77 

the  moment.  There  are,  however,  as  many  different  constitutions 
and  as"  many  different  anatomical  and  pathological  possibilities 
for  the  occurrence  of  the  reaction  as  there  are  different  in- 
dividuals. The  healthy  human  body  is  no  constant  quantity, 
and  the  tubercular  subject  is  a  highly  variable  one,  making  it 
altogether  impossible  to  fix  a  maximal  dose  in  diagnosis  applic- 
able to  all  cases. 

Attempts  have  also  been  made,  and  we  have  ourselves  tried 
for  years,  to  draw  conclusions  about  the  activity  or  latency  of  the 
tubercular  process  from  the  dose  which  first  produces  a  reaction. 
We  have  not  been  successful. 

In  our  opinion  the  question  about  which  dispute  centres 
cannot  be:  What  is  the  limiting  dose  in  tuberculin  diagnosis? 
But  it  must  rather  be  put  thus  :  With  what  quantity  of  tuber- 
culin do  we  most  nearly  approach  the  limiting  dose  to  which 
one  must  go  to  attain  a  specific  reaction  and  beyond  which  the 
healthy  individual  also  reacts  ? 

Our  own  observations  in  this  direction,  extending  over 
years,  have  shown  that  cases  with  clinical  suspicion  of  tuber- 
culosis, which  quite  failed  to  react  to  a  final  dose  of  less  than 
10  c.mm.,  showed  later  on  well-marked  tubercular  foci  at  the 
suspected  spots,  with  bacilli  in  the  sputum. 

In  two  further  cases  with  positive  history  but  doubtful 
physical  signs,  there  was  no  reaction  to  o"2,  i,  and  5  c.mm. 
tuberculin,  whereas  the  fourth  injection  of  10  c.mm.  gave  rise  to 
typical  reactions ;  the  pulmonary  foci  which  were  then  evident  in 
both  cases  established  their  existence  by  the  discovery  of  bacilli 
in  the  sputum.  The  reaction  curve  of  such  a  case  is  illustrated 
by  Chart  7. 

Further  reasons  may  be  given  for  fixing  the  maximal  dose  at 
10  c.mm.  Wassermann  and  Bruck  observed  two  cases  in  the 
initial  stage  which  only  reacted  to  10  c.mm.  of  tuberculin  ;  in 
both  cases  before  the  injection  the  examination  of  the  serum 
showed  the  absence  of  any  antibodies,  whereas  after  the  injection 
they  were  proved  to  be  present.  We,  too,  have  repeatedly  seen 
focal  reactions  which  point  to  a  fresh,  active  tubercular  process, 
taking  place  only  after  the  injection  of  10  c.mm.  of  tuberculin, 
an  observation  which  has  lately  been  confirmed  by  the  Tubingen 
Medical  Clinic.     (See  Chart  No.  8.) 

It  is  a  well-known  fact  that  of  recent  cases  a  large  proportion 
reacts  to  small  doses  of  tuberculin  with  quick  and  generally 
pronounced  rise  of  temperature,  whilst  older  and  less  active 
processes  frequently  react  only  to  higher  doses,  and  this  after  a 
longer   interval.      However,    considering    the    frequency    of    old, 


78  TUBERCULIN    IN    DIAGNOSIS    AND   TREATMENT 

dried    up    tubercular    foci    (especially    in    the    tracheo-bronchial 

glands),  it  cannot  be  the  aim  of  a  diagnostic  method  to  rake  up 

such  cases  and  make  them  submit  to  a  course  of  treatment,  the 

matter   being   mostly    no    longer    of   practical    import.     But    this 

will  certainly  be  promoted  by  the  repetition  of  the  maximal  dose 

of  10  c.mm.  of  tuberculin. 

_  r         The    dosage    in    adults    for    the    purposes 

Summary  of  c      ...  .  ,u         ,  •      , 

7  of     diagnosis     mav     then     be     summarized 

Dosage.  thus  ._ 

2 

Initial  dose 0-2  c.mm.  (^  mg.) 

1st  increase 1*0  c.mm.    (1  mg.) 

2nd  increase...          '..          ...    5*0  c.mm.  (5  mg.) 
Limiting  dose  10-0  c.mm.  (10  mg.) 

r     But  it  must  be  noted  that  reaction  to  one 
"  of  the  tuberculin  doses  mentioned  does  not 

point  with  absolute  certainty  to  active 
tuberculosis,  requiring  treatment.  We  are  specially  warned 
in  this  respect  by  the  observations  made  during  many  years 
by  Franz  [93]  on  a  thousand  soldiers  injected  with  tuberculin 
for  purposes  of  diagnosis.  In  a  Bosnian  infantry  regiment, 
which  was  recruited  from  a  district  infested  with  tuberculosis, 
61  per  cent,  out  of  400  recruits  gave  a  positive  reaction  to 
subcutaneous  doses  of  tuberculin  up  to  3  c.mm.  In  a  Hun- 
garian regiment  from  a  neighbourhood  where  there  was  less 
tuberculosis,  the  percentage  of  reactions  went  down  to  38  per 
cent. — a  proof  that  the  frequency  of  the  tuberculin  reaction 
coincides  with  the  spread  of  tuberculosis  among  the  inhabitants. 
Only  those  recruits  were  injected  who,  on  clinical  examination, 
showed  no  signs  of  disease  in  the  individual  organs.  Only  a 
small  proportion  of  those  in  whom  reaction  took  place  suffered 
in  the  following  years  from  clinically  manifest  tuberculosis,  and 
moreover  the  Bosnian  men  more  frequentlv  (7 '6  per  cent.)  than 
the  Hungarian  (3*2  per  cent.),  corresponding  with  the  diagnostic 
figures.  From  these  facts  Franz  rightly  deduces  that  from  the 
tuberculin  reaction,  that  is,  from  the  quantity  of  tuberculin 
necessary  to  produce  the  reaction  and  from  the  intensity  of  the 
symptoms  of  reaction,  "  no  definite  conclusions  can  be  drawn  as 
to  the  character  and  later  development  of  the  tubercular 
disease  in  Stadium  I."  This  conclusion  of  Franz  is  in  complete 
accordance  with  what  we  have  repeatedly  emphasized  for  years, 
but   which    has   certainly   been    overlooked   by   some   physicians. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  79 

We  will  therefore  repeat  once  more  here  :  The  subcutaneous 
tuberculin  reaction,  as  such,  tells  us  nothing  certain  as  to  the 
activity  or  inactivity  of  the  process.  It  only  tells  us  whether  the 
person  tested  is  infected  with  tuberculosis,  which  may  be  latent 
and  active  or  latent  and  inactive.  Whether  the  former  or  the 
latter  is  the  case  must  be  decided  by  clinical  observation  and  by 
consideration  of  the  history  of  the  patient.  Therefore  the  value 
of  the  tuberculin  diagnosis  will  always  remain  conditional,  no 
matter  which  of  the  tests  is  used,  but  the  value  of  the  subcutaneous 
test  is  much  higher  than  that  of  the  local  tests,  because  the 
dosage  is  exact  and  the  absorption  of  the  injected  tuberculin 
uniform.  So  after  the  experience  of  thousands  of  cases  the  con- 
clusion may  be  drawn  that  several  and  increased  doses  may 
be  necessary  to  show  the  presence  of  active  tuberculosis,  that 
with  a  dose  of  10  c.mm.  tuberculin  and  less,  only  those  with 
tubercular  foci  react.  We  also  know  that  rapid  reaction  to  small 
subcutaneous  doses  of  tuberculin  denotes  a  more  recent  disease, 
delayed  reaction  to  higher  doses,  older  chronic  processes.  Be- 
tween them  there  are  various  grades.  And  as  the  dividing  line 
between  active  and  inactive  tuberculosis  is  by  no  means  sharply 
drawn,  but  on  the  contrary  is  extraordinarily  variable,  the  value 
of  the  tuberculin  reaction,  as  being  in  itself  and  alone  capable  of 
proving  the  existence  of  active  tuberculosis,   is  too  schematic. 

K,  .x  It  would,   however,  be  a  crime  against  the 

Necessity 

spirit  of  diagnosis  to  let  what  has  been  said 
of  Careful 

here    prove    an    insurmountable    barrier    to 

Judgment.  tjie    use    0f    tuberculin.      In    biological    re- 

actions there  is  no  rigid  scheme,  applicable  to  all  cases ;  room 
must  be  left  for  the  judgment  of  the  physician  in  each  individual 
case,  of  which  the  practitioner  experienced  in  tuberculin  will  be 
able  to  take  more  advantage  than  the  beginner.  Thus  it  will  be 
understood  that  in  certain  cases  a  third  dose  of  2 '5  c.mm.  and  a 
final  one  of  5  c.mm.  should  be  selected,  e.g.,  during  the  years  of 
development  in  specially  weakly  persons,  those  who  have  a  scare 
of  consumption,  excitable  neurasthenics,  and  so  on.  The  pre- 
caution should  then  be  taken  of  keeping  these  patients  under 
observation  and  in  doubtful  cases  the  diagnostic  injections  should 
be  repeated. 

Safety  of  the        Hammer    [94]    and    Junker    [95]    in    their 
out-patient     practice     in     the     Heidelberg 
Hospital    observed    no    important    disturb- 
ance of  health  following  the  use  of  diagnostic   tuberculin,   and 
never  any  permanent  damage  or  exacerbation   of  the  tubercular 
process,  and  they  therefore  also  agree  that  the  use  of  tuberculin 


80  TUBERCULIN    IN   DIAGNOSIS    AND   TREATMENT 

injections  in  diagnosis  is  perfectly  suitable  for  the  general 
practitioner.  Bulle  [96],  from  his  own  experience,  lays  stress 
upon  the  fact  that  the  use  of  tuberculin  injections  makes  diagnosis 
much  easier  for  the  general  practitioner  and  the  club  doctor. 

The  tuberculin  reaction  after  subcutaneous 
The  Tuberculin       injection    is    a    specific    reaction    of    hyper- 
Reaction,  susceptibility  on  the  part  of  the  tubercular 

subject,  just  as  is  the  case  after  cutaneous 
and  conjunctival  tuberculin  inoculation.  So  that  the  phenomenon 
is  uniform  and  the  dissimilarities  in  the  reactions  are  not  qualita- 
tive but  only  quantitative,  caused  by  the  difference  in  dosage 
and  the  absolutely  different  conditions  as  regards  the  absorption 
of  the  tuberculin  according  to  the  site  of  application  and  the 
method  used.  Moreover,  all  tuberculin  reactions  essentially  give 
results  of  equal  value,  which  are  modified  in  various  ways  by 
external  causes  (site  of  inoculation,  dose  of  tuberculin,  conditions 
of  absorption). 

Whereas  the  local  tuberculin  tests — used  lege  artis — take 
effect  at  the  spot  selected  far  from  the  real  seat  of  the  disease, 
the  subcutaneous  test  attacks  the  diseased  focus  direct  and  in 
the  end  produces  a  focal  reaction.  The  focal  reaction  is  therefore 
the  distinguishing  and  at  the  same  time  the  most  important 
characteristic  of  the  subcutaneous  tuberculin  test,  so  important 
that  from  the  diagnostic  point  of  view  the  physical  proof  of  the 
focal  reaction,  to  which  no  exception  can  be  taken,  can  be  placed 
on  an  equal  footing  with  the  proof  of  the  presence  of  tubercle 
bacilli. 

The   subcutaneous     tuberculin     reaction     is 

made  up  of  the  following  four  components  : 

(1)  The  rise  of  the  temperature  of  the  body  (febrile  reaction). 

(2)  The  disturbance  of  the  physical  well-being  (general  re- 
action). 

(3)  The  local  inflammatory  reaction  at  the  site  of  injection 
(needle-track  reaction). 

(4)  The  inflammatory  reaction  at  the  focus  of  the  disease 
(focal  reaction). 

These  reactions  may  appear  all  at  the  same  time,  or  each 
separately,  or  several  combined.  The  febrile  and  general  re- 
actions are  the  most  regularly  observed. 

_,_.       _  .    ..       .     Fever   is,    of   all    the   svmptoms   of   the   re- 

action,  the  most  regular,  the  most  objective 

and  easily  measured.     In  general  a  reaction 

is  considered  positive  when  there  is  a  rise  of  at  least  0*5°  on  the 


THE    SPECIFIC    DIAGNOSIS    OF   TUBERCULOSIS  8 1 

highest  temperature  recorded  before  the  injection.  According 
to  the  height  of  the  fever,  the  reaction  is  denoted  as  slight  (up 
to  380),  moderate  (up  to  390),  or  severe  (over  390). 

The  beginning,  height,  and  duration  of  the  fever  vary  within 
such  wide  limits  that  it  is  not  possible  to  speak  of  a  typical 
reaction-curve.  Most  typical  is  rapid  rise,  slower  fall,  normal 
temperature  reached  after  twenty-four  hours  or  less  often  on  the 
second  day. 

The  rise  of  temperature  begins  on  the  average  six  to  eight 

hours  after  the  injection,  but  cases  also  occur  in  which  it  begins 

within   four   hours   or   is   delayed   for   thirty.     The   acme   of   the 

reaction  is  reached  on  the  average  in  about  nine  to  twelve  hours, 

whilst  its  duration   may  be  thirty  hours   or   longer,    but  several 

days'  or  weeks'  fever  is  unusual.     Uniformity  is  observable  in  so 

far  as  the  smaller  the  dose  of  tuberculin  administered,  the  later 

the  reaction  begins  and  the  later  it  reaches  its  height. 

_  ...  The   rise  of   temperature   is  also  as  a   rule 

Cumulative  ..    .  ,  „       ,       ,  D 

slighter  the  smaller  the  dose.     But  cases  are 

always  occurring  in  which  even  the  smallest 
doses  produce  rapid  and  considerable  rise  of  temperature.  It  is, 
however,  of  practical  importance  not  to  construe  a  rise  too  rigidly. 
In  view  of  the  great  instability  of  the  body  temperature,  especially 
in  suspected  cases  of  tuberculosis,  exercise,  mental  emotion,  &c, 
may  alone  give  rise  to  the  half  degree  of  variation,  especially 
when  they  coincide  with  the  physiological  rise  of  temperature  after 
meals  or  in  the  evening.  Remembering  the  objection  raised  on 
the  ground  of  the  occurrence  of  anaphylaxis,  there  is  now  every 
reason  to  keep  specially  in  the  foreground  the  promptness  and 
definiteness  of  the  febrile  reaction  as  the  certain  proof  of  the 
presence  of  a  tubercular  focus  in  the  body.  And  in  all  cases 
where  there  is  any  doubt  one  should  not  be  content  with  the  half 
degree  of  elevation,  but  rather  wait  until  the  temperature  has 
returned  to  the  normal  and  then  repeat  the  same  dose.  Then  in 
active  tuberculosis  cumulative  action  almost  always  makes  itself 
seen  in  the  form  of  a  more  considerable  rise  of  temperature  (see 
Charts  5  and  10). 

Special    note    must    be    made    of    pseudo- 

Pseudo-  reactions.     These  may  now  and  then  be  due 

reactions.  to     intercurrent     febrile     affections,     whose 

origin  is  not  at  once  apparent,  simulating 
a  tuberculin  reaction.  We  mention  as  an  example  a  case  in  which 
an  inflammatory  swelling  of  the  gums  gave  rise  to  a  pseudo- 
reaction  (see  Chart  No.  9). 

6 


82  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

The  so-called  psychogenic  and  suggestive  rises  of  tempera- 
ture belong  to  the  same  category.  They  occur  in  persons  with 
signs  of  nervous  instability — neurasthenics,  hysterical  persons, 
and  those  with  erethitic  constitution — and  may  be  produced  by  the 
puncture  of  the  needle  or  the  injection  of  a  few  divisions  of  mere 
water  (injectio  vacua).  Such  cases  are,  however,  by  no  means  so 
frequent  as  to  necessitate  the  injection  of  wrater  in  every  case 
before  the  diagnostic  dose  of  tuberculin  is  given  in  order  to 
prevent  the  mistaking  of  a  psychogenic  for  a  specific  reaction.  It 
is  only  necessary  to  avoid  verbal  suggestions  of  any  kind  w-hich 
in  susceptible  natures  may  cause  fluctuations  of  temperature. 
When  psychogenic  fever  is  suspected,  we  recommend  that  the 
temperature  be  not  taken  by  the  patient  himself  and  that  an 
injectio  vacua  be  given  without  his  knowledge  of  its  nature  subse- 
quently to  the  tuberculin  injection.  If  fever  then  occurs,  the  first 
reaction  was  psychogenic;  if  there  is  no  fever,  the  first  tuberculin 
dose  is  repeated,  and  it  is  characteristic  of  cases  of  psychogenic 
reaction  that  the  cumulative  action  on  repetition  does  not  occur. 
The  diagnostic  difficulties  are  such,  however,  that  diagnosis  of 
such  cases  should.be  left  to  a  sanatorium  (see  Chart  No.  10). 

It  must  be  added  that  in  patients  with  nervous  instability  it 
is  often  impracticable  to  bring  the  temperature  down  to  or  below 
37'3°  C.  (mouth).  In  such  cases  it  is  occasionally  justifiable  to 
proceed  with  the  injection  with  temperatures  of  37'3°  to  37'5°  C. 
(mouth). 

The  general  reaction  is  the  result  of  a  toxic 

The  General         action  on  the  human  organism  common  to 
Reaction.  all  bacterial  products,  and  finds  expression 

chiefly  in  a  disturbance  of  the  general  con- 
dition. It  follows  from  this  that  the  quantity  of  tuberculin 
injected  for  diagnostic  purposes  must  be  such  that  on  the  one 
hand  enough  specific  substance,  on  the  other  not  too  much  toxic 
substance,  is  administered.  According  to  R.  Koch,  the  specific 
action  of  tuberculin  is  to  be  expected  and" in  adults  the  toxic  action 
excluded  with  a  dose  of  10  c.mm. 

Disturbance  of  the  general  health  by  various 
Symptoms.  symptoms   is  the  most   regular  accompani- 

ment of  the  tuberculin  reaction.  The 
typical  severe  reaction  begins  with  rigor  and  subsequent  feeling 
of  warmth,  or  with  shivering  and  feeling  of  chilliness  with 
malaise,  giddiness,  nausea  or  vomiting.  At  the  height  of  the 
reaction  the  usual  accompaniments  are  severe  headache  and  pains 
in  the  limbs,  pain  of  a  dragging  or  stabbing  character  in  the 
affected  organ,  palpitation,  loss  of  appetite,  thirst,  sleeplessness, 
lassitude;  in  short,  a  general  feeling  of  illness  of  greater  or  less 


THE   SPECIFIC    DIAGNOSIS    OF   TUBERCULOSIS  83 

degree.  With  the  fall  of  temperature,  the  symptoms  give  place 
to  a  feeling  of  general  weakness,  which,  in  its  turn,  usually 
passes  off  with  return  to  normal  temperature.  The  severest 
reactions  mostly  disappear  in  an  incredibly  short  time. 

With  regard  to  the  intensity  of  the  symptoms  there  is  great 
variability  and  it  is  not  exclusively  determined  by  the  height  of 
the  reaction.  Not  infrequently,  in  spite  of  severe  reaction,  there 
is  little  feeling  of  illness;  and,  on  the  other  hand,  with  slight 
febrile  reaction  the  whole  gamut  of  symptoms  enumerated  may 
be  complained  of.  In  this  respect  individual  differences  and 
susceptibilities  play  a  great  part  and  occasion  the  incidence  of 
symptoms  in  various  organs,  e.g.,  gastric  and  intestinal  sym- 
ptoms, disturbances  of  the  bladder,  of  the  central  nervous  system, 
sensory  or  motor,  &c.  To  the  most  frequent  objective  symptoms 
belong  acceleration  of  the  pulse  and  respiration. 

In  the  urine,  albumin  may  very  occasionally  be  present  as  a 
febrile  symptom.  The  rare  occurrence  of  loss  of  consciousness, 
of  stupor,  of  swelling  of  the  spleen  or  of  the  lymph  glands  in 
the  region  of  the  injection,   need  onlv  be  mentioned. 

.         .  The    needle-track    reaction    at    the   place   of 

injection,  a  local  infiltration  of  the  subcu- 
taneous tissues,  is  the  most  frequent  objec- 
tive symptom,  and  consists  of  swelling  and  painfulness  at  the 
injection  site.  When  old  tuberculin  is  emploved,  a  more  or  less 
distinct  local  infiltration  occurs  with  such  regularity  with  every 
positive  tuberculin  reaction  that  its  non-occurrence  almost  points 
to  a  pseudo-reaction.  With  albumose-free  tuberculin,  the  needle- 
track  reaction  is  decidedly  less  frequent  and  less  severe,  often 
invisible  and  only  signalized  by  slight  painfulness. 

The  focal   reaction   has  an  advantage  over 
Focal  the   febrile,    general   and   local   reactions   in 

Reaction.  that  it  gives  a  clue  to  the  site  of  the  tuber- 

cular process  in  the  body.  Certain  pheno- 
mena in  the  sequelae  of  the  reaction  have  a  significance  in 
localizing  the  disease,  e.g.,  spinalgia  or  tenderness  over  the 
spinous  processes  and  the  sternum,  associated  with  a  feeling  of 
tension  in  the  chest,  may  be  caused  by  increase  in  the  intra- 
thoracic pressure  from  swelling  of  the  thoracic  lymph  glands,  a 
focal  reaction.  Disturbances  of  heart  and  stomach  may  be 
referred  to  direct  irritation  of  the  vagus,  also  from  lymph  glands 
in  a  state  of  inflammatory  reaction. 

In  fine,  every  individual  focal  reaction  which  remains  limited 
to  the  tubercular  process  and  has  the  course  of  a  fleeting  inflam- 
matory affection  will  give  rise  to  different  symptoms,   according 


84  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

to  the  structure  and  function  of  the  particular  organ  with  which 

it  is  connected.     On  this  rests,  in  no  small  degree,  the  advantage 

of  the  subcutaneous  administration.        In   the   Special   Part,   we 

shall  return  to  the  most  noteworthy  symptoms  in  connection  with 

the  several  organs. 

_  Special  treatment  of  the  tuberculin  reaction 

Treatment  .  ,  r^,  jV- 

is,   as  a  rule,   unnecessary,      the  condition 

of  the  patient  determines  whether  rest  in 
Reaction,  j-,^  js  necessary  or  not;  there  is  no  justifi- 

cation for  the  measure  of  confining  him  to  bed  during  the  whole 
period  of  the  injections.  For  severe  headache,  in  addition  to  the 
ice-bag,  phenacetin,  antipyrin,  antifebrin,  lactophenin  (0*25  to 
o'5  grm.  once  or  more)  or  migranin  (1  grm.  once  or  twice)  may 
be  given  ;  for  very  high  fever  small  doses  of  pyramidon  (o'i  grm., 
repeatedly).  In  general,  drugs  should  not  be  given  until  the 
highest  point  of  the  temperature  curve  appears  to  have  been 
passed. 

Special  symptoms  require,  when  necessary, 
of  Special  their  appropriate  treatment  :  e.g.,  sleepless- 

Symptoms,  ness     with     bromide,     bornyval,     dormiol, 

veronal,  or  adalin ;  intestinal  disturbance 
with  opium,  bismuth  or  calomel.  The  subject  of  a  reaction  is 
certainly  a  sick  person,  but  one  who  soon  recovers.  After  the 
reaction  has  passed  off,  the  patient  often  shows  and  acknowledges 
a  special  feeling  of  well-being,  a  fact  noted  by  R.  Koch  in  his 
first  publication,  and  which  is  brought  about  by  the  removal  of 
toxins  from  the  organism  in  general  and  the  consequent  improve- 
ment or  even  complete  disappearance  of  all  kinds  of  complaints 
which  had  chiefly  been  referred  to  the  diseased  focus.  This 
happens  most  frequently  after  severe  reactions. 

Saathoff  [07]  discovered  by  very  careful  metabolic  experiments  that  in 
the  tuberculin  reactions,  besides  the  feeling  of  general  well-being  after  the 
fall  of  temperature,  there  is  almost  always  during  the  reactionary  stage, 
in  spite  of  the  fever,  a  rapid  and  lasting  increase  in  weight,  which  he  attri: 
butes  in  the  main  to  a  diminution  in  the  processes  of  combustion  in  the  body, 
to  the  retention  of  water  and  deposits  of  salt.  He  concludes  from  this  that 
the  tuberculin  reaction  brings  about  a  very  great  change  in  metabolism, 
especially  in  mineral  metabolism,  and  by  so  doing  leads  to  a  distinct  turn 
for  the  better  in  the  course  of  the  disease.  We  can  confirm  this  from  the 
observation  of  300  to  400  cases  annually.  Increases  in  weight  of  two,  three 
and  more  kilogrammes  are  the  regular  thing  during  the  diagnostic  use  of 
tuberculin;  no  increase  or  a  decrease  is  quite  exceptional.  And  in  many 
cases  we  also  have  had  the  impression  that  even  by  the  first  tuberculin 
reaction  we  have  materially  benefited  the  patient.  This  is  also  quite  in 
conformity  with  the  observations  made  by  Hager,  Longard  and  others, 
especially  in  anaemic  and  chlorotic  girls  and  in  those  suffering  from  gastric 
troubles,  suspected  of  tuberculosis. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  8.5 

We  have  not  observed  serious  or  permanent  harm  even  after 
the  severest  tuberculin  reaction,  above  all  no  permanent  disturb- 
ance of  the  functions  of  the  heart,  the  lungs,  the  pleura,  the 
kidneys,  or  nervous  system.  Basing  our  opinion  on  the  observa- 
tion of  several  thousands  of  tuberculin  reactions,  we  would 
specially  emphasize  the  point  and  advise  the  critical  consideration 
of  every  individual  case  without  adopting  straightway  the  lay 
point  of  view  that  a  post  hoc  proves  also  a  propter  hoc.  This 
warning  seems  specially  necessary  in  view  of  the  statements  of 
Ulrici  at  the  sixth  Congress  of  Sanatorium  Physicians ;  we  shall 
return  to  this  in  the  Special  Section. 

_  Contra-indications  can  be  specially  sharply 

enunciated    now    that    we    have    other    dia- 

gnostic  methods  giving  only  a  local  re- 
action. Although  after  countless  observations  the  phrases 
"  generalization  of  the  tubercular  poison  "  or  "  mobilization  of  a 
hostile  army  "  have  become  devoid  of  all  foundation,  yet  the 
precept  "  primum  nihil  nocere  "  remains  of  the  first  import  to 
the  diagnostician.  He  must  first  of  all  decide  what  are  the  con- 
ditions which,  under  all  circumstances,  contra-indicate  the 
diagnostic  use  of  tuberculin. 

The    first    contra-indication    and    the    one 
(1)   Fever.  occurring  most  frequently  in   practice  is  a 

rise  of  temperature  above  370  C.  in  the  axilla 
or  above  37 '30  C.  in  the  mouth.  This  is  based  on  the  consideration 
that  a  variable  temperature  above  the  normal  limit  renders 
impossible  a  proper  estimation  of  the  significance  of  a  febrile 
reaction  after  the  injection.  And  besides  this,  reactive  processes 
taking  place  in  the  system  and  giving  rise  to  fever  disturb  the 
action  of  the  tuberculin.  Only  in  subjects  of  unstable  tempera- 
ment— nervous,  neurasthenic,  hysterical  and  erethitic  patients  and 
those  with  a  morbid  dread  of  tuberculosis — may  exception  be 
made;  even  then  the  temperature  must  not  exceed  37"5°  C.  nor  be 
referable  to  the  focus  which  raises  the  suspicion  of  tuberculosis. 

/ri.    ~.  .  Secondly,   tuberculin  is  contra-indicated  in 

(2)  Diagnosis         ,.  J.      .  .  ,  ,.    .     , 

'         .  diagnosis    in    patients    where    the    clinical 

history  or  the  physical  signs  alone  make  the 

other  Grounds.      diagnosis     certain,      and     where     tubercle 

bacilli    are    present    in    the    sputum.       Tuberculin    diagnosis    is 

generally  superfluous  in  these  cases.   The  clinical  history  must  be 

taken  and  physical  examination  carried  out  with  the  utmost  care 

as  well  as  repeated  examinations  of  the  sputum  made  (antiformin 

method,    Gram-staining,   &c.)  before  the  syringe  is  resorted  to. 

It   would  be   a   perversion    to   see    in    the    tuberculin   reaction    a 


86  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

convenient  way  of  avoiding  the  well-tried  older  methods.  "  Not  in 
the  alternative  use,  but  in  the  combination  of  the  various  methods 
of  clinical  examination,  lies  the  value  of  additions  to  our  diagnostic 
armament."  Tuberculin  is  not  designed  to  replace  but  to 
supplement  the  other  approved  methods  of  physical  diagnosis, 
and  to  enter  the  field  when  they  fail.  The  subcutaneous  tuber- 
culin test  is  a  single  aid  to  diagnosis  and  the  last  to  be  employed. 

Thirdly,     recent    haemoptysis    in    cases    of 
(3)  Haemoptysis,     suspected     pulmonary     tuberculosis     is     a 

contra-indication.  The  possibility  of  the 
occurrence  of  a  haemoptysis  following  on  the  rapidly  rising  dosage 
of  diagnostic  tuberculin  must  be  admitted.  A  violent  local  reaction 
may  cause  destruction  of  tubercular  tissue  and  hence  increase 
the  likelihood  of  blood  being  effused.  The  stronger  cough  effort 
which  may  occur  during  the  reaction  must  also  be  considered,  and 
the  possibility  of  severe  haemoptysis  is  made  greater.  It  will 
generally  be  impossible  to  decide  whether  post  hoc  or  propter 
hoc,  but  the  occurrence  of  a  considerable  haemorrhage  is  an  event 
of  such  serious  moment  that  everything  must  be  scrupulously 
avoided  which  might  tend  in  this  direction.  In  cases,  therefore, 
where  the  sputum  contains  even  traces  of  blood,  rest  in  bed  should 
be  prescribed  until  these  have  disappeared,  and  only  after  several 
days  out  of  bed  without  the  blood  returning  should  tuberculin 
diagnosis  be  commenced ;  and  then  with  great  care,  and  only  as 
a  last  resort  to  establish  a  diagnosis. 

The  physician  should  always  assure  himself  personally  of 
the  character  of  the  sputum  ;  exaggeration  and  concealment  are 
frequent  in  this  respect,  even  without  intention  of  bad  faith. 
Fairly  often  the  appearance  and  smell  of  the  blood-stained  sputum 
will  leave  no  doubt  that  the  blood  has  its  origin  in  neglected 
gums  or  in  chronic  inflammatory  conditions  of  larvnx,  pharynx, 
or  naso-pharynx.  Here,  of  course,  there  is  no  contra-indication. 
On  the  other  hand,  the  blood  coughed  up  may  have  the  charac- 
teristics of  a  haemoptysis,  and  then  the  clinical  history  and 
physical  signs  will  as  a  rule  assure  the  diagnosis. 

...    I_l       ,  Fourthly,  heart  disease.     When  it  is  borne 

.  in  mind  that  in  isolated  cases  the  tuberculin 

reaction  itself  has  resulted  in  conditions  of 
angina  pectoris,  precordial  distress,  dilatation  of  the  ventricles 
and  irregularity  or  dicrotism  of  the  pulse,  a  sound  or,  at  any  rate, 
functionally  perfect  heart  must  be  held  to  be  a  sine  qua  non  of 
tuberculin  diagnosis.  Slight  disturbances  of  the  heart's  action, 
especially  those  of  a  functional  nature,  occur  so  frequently  with 
early  tubercle  that  on  practical  grounds  alone  they  should  not 


THE   SPECIFIC   DIAGNOSIS    OF   TUBERCULOSIS  87 

exclude  the  application  of  the  method.  And  in  practice  this  is 
altogether  unnecessary.  But  severe  valvular  disease,  and  condi- 
tions such  as  myocarditis,  fatty  or  weak  heart  contra-indicate  this 
method  of  diagnosis. 

Fifthly,  renal  disease.  Even  in  patients 
^  \  with  sound  kidneys  albuminuria  may  occur, 

Disease.  but  ge^cm,  at  t^e  height  of  the  tuberculin 

reaction  ;  this  is  a  transitory  febrile  phenomenon  and  therefore  of 
no  significance.  It  is  also  possible  that  this  passing  albuminuria 
is  connected  with  the  lowered  systolic  and  raised  diastolic  blood- 
pressure  seen  after  tuberculin  injections.  Reznicek's  [98]  experi- 
ments show  that  in  chronic  renal  inflammation  the  systolic  pres- 
sure is  considerably  reduced  even  by  small  tuberculin  doses. 
Therefore,  in  cases  of  existing  renal  disease  of  non-tubercular 
nature,  serious  damage  may  occur  as  a  sequel  to  the  tuberculin 
reaction;  e.g.,  increase  of  albumin,  of  casts  and  other  formed 
elements,  hasmaturia,  &c.  Hence  an  examination  of  the  urine 
must  precede  the  application  of  the  method,  and  any  form  of 
nephritis  be  held  to  contra-indicate  it. 

Sixthly,  epilepsy.  The  possibility  of  the 
(6)   Epilepsy.         irritative   action    of   the   tuberculin    reaction 

on    the    locus    minoris    resistentice    of    the 

epileptic   cannot    be    gainsaid;    and    in    actual    fact    it    has   been 

observed  that  after  being  absent  for  years  epileptiform  seizures 

may  occur  as  a  sequel  to  the  injection.     Epileptics  suspected  of 

tuberculosis  should  not  be  exposed  to  this  risk ;  the  method  must 

be  abandoned. 

,_.    l,      .     .  Hysteria  and  severe  neurasthenia  may  also 

(7)   Hysteria  as  a    ,    J  .    ,  ....  J    . 

'  be  regarded  as  contra-indications  now  that 

Contra- 

we  possess  the  local  tuberculin  tests,  since 

indication.  jn    a    considerable    percentage    of    cases    a 

tuberculin  reaction  may  be  simulated  by  oscillations  of  tempera- 
ture due  purely  to  psychical  causes  and  without  tuberculosis 
being  present.  But  here  too  when  the  local  tests  give  a  doubtful 
result  the  subcutaneous  injection  comes  into  its  rights ;  only,  for 
the  reasons  given,  it  must  be  carefully  and  critically  done  and 
control  injections  of  water  given. 

/0\  r*  1  Finally,    the   tuberculin    reaction   is   contra- 

(8)  General  .  f 

indicated,    from   reasons   of   expediency  as 

well  as  on  scientific  grounds,  where  miliary 
indications.  tuberculosis   is   suspected,    since   its   down- 

ward course  might  be  accelerated ;  where  there  is  suspicion  of 
intestinal  tuberculosis,  and  the  presence  of  deep  intestinal  ulcers 
can  be  deduced  from  special  areas  of  tenderness  to  which   the 


88  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

resulting  localized  peritonitis  has  given  rise ;  in  convalescents 
and  weakly  persons  immediately  after  severe  diseases  (typhoid, 
scarlatina,  pneumonia,  pleurisy,  peritonitis,  perityphlitis,  gastric 
ulcer,  &c.) ;  and  finally  in  patients  with  severe  diabetes,  tendency 
to  apoplexy,  marked  arteriosclerosis  or  amyloid  degeneration  of 
the  abdominal  viscera. 

The  indications  for  the  subcutaneous  appli- 
Indications.  cation    of    tuberculin    in    diagnosis    are    in 

general  :  (a)  To  make  an  early  diagnosis  in 
doubtful  cases ;  (b)  to  determine  the  course  of  treatment  where 
difficulty  in  making  a  differential  diagnosis  is  present. 

This  general  statement  as  to  the  indications  may,  apart  from 
the  contra-indications  already  mentioned,  now  be  limited  in  the 
direction  of  leaving  the  subcutaneous  test  to  the  last,  whilst  it 
remains  the  most  certain  of  the  methods.  It  decides  in  cases 
where  a  focal  reaction  gives  promise  of  help  in  localization,  and 
where  the  cutaneous,  percutaneous,  or  conjunctival  tests  are 
contra-indicated  or  lead  to  no  certain  result. 

We  especially  emphasize  here  this  diagnostic  importance  of  the  subcu- 
taneous tuberculin  test,  because  it  has  been  done  away  with  at  the  veterinary 
stations  on  the  frontier  and  at  the  veterinary  quarantine  stations.  This 
might  give  rise  to  the  impression  that  tuberculin  had  proved  a  failure  in 
diagnosis.  But  this  is  not  the  case.  On  the  contrary,  according  to  Schutz 
[99],  the  official  tests  by  Casper  and  Olt  on  the  cattle  imported  from  Denmark 
show  that  only  2  to  3  per  cent,  of  animals  which  reacted  in  the  prescribed 
manner  to  the  injection  of  tuberculin  and  were  slaughtered  showed  no 
traces  of  tubercular  changes.  "  Consequently  tuberculin  can  be  looked  upon 
as  an  almost  infallible  means  of  determining  the  presence  of  tuberculosis 
in  cattle  "  (Schutz).  The  chief  reason  why  this  method,  which  even  in  very 
high  doses  never  involved  any  danger  to  the  animal  inoculated,  has  been 
officially  abandoned  is  this  :  that  the  cattle  dealers,  shortly  before  the 
official  test,  gave  tuberculin  injections  on  their  own  account.  By  this  means 
they  were  able  to  establish  a  certain  degree  of  tuberculin  tolerance  and  in 
increasing  measure  deprive  the  official  test  of  its  value.  It  remains  to  be 
seen  whether  the  veterinary  tuberculin  diagnosis  in  frontier  and  quarantine 
stations  will  be  permanently  abandoned.  We  fear  that  the  abolition  of  the 
tuberculin  tests  will  only  help  to  promote  the  importation  of  tubercular 
cattle  from  other  countries.  The  subcutaneous  tuberculin  reaction  (also 
called  the  "  thermal  "  reaction  in  veterinary  medicine)  gives  useful  results 
also  in  the  diagnosis  of  tuberculosis  in  horses,  sheep,  goats,  pigs,  dogs, 
rabbits,  and  guinea-pigs;  it  only  fails  in  fowls  and  turkeys. 

The  Method  *n  c^^^ren  t^ie  doses  of  tuberculin  for  the 

adult  are  to  be  reduced  by  one-half  :  betnn 
in  the  Case  of         .,,      .  , 

with  o  1  c.mm.,  increase  to  05  c.mm.,  then 

Children.  to  2-^  C-mm>)  an(^  finally  to  5  c.mm. 

Engel  [100]  urges  against  this  dosage  that  the  decrease  in  the 


THE   SPECIFIC   DIAGNOSIS    OF   TUBERCULOSIS  89 

dose  for  children  is  not  justified,  because  the  susceptibility  to 
tuberculin  depends  on  the  extent  of  the  tubercular  process  and 
not  on  the  age  of  the  particular  subject,  and  that  the  typical  chil- 
dren's tuberculosis  is  characterized  by  great  tolerance  of  tuber- 
culin. He  is  right  in  both  statements;  but  this  will  not  lead  us 
to  fix  the  tuberculin  dose  for  purposes  of  diagnosis  at  the  same 
height  as  for  adults.  For  in  the  first  place  a  larger  dose  may  pro- 
duce a  purely  toxic  action.  And  secondly,  we  do  not  know 
before  the  injection  of  tuberculin  whether  it  is  a  case  of  tubercu- 
losis, let  alone  a  case  of  typical  children's  tuberculosis,  very 
tolerant  of  tuberculin.  It  is  also  in  keeping  with  our  pharmaco- 
logical views  to  give  a  smaller  dose  of  a  toxic  substance  to  a  child 
than  to  an  adult.  We  therefore  stand  to  our  proposal  to  give 
children  as  a  first  diagnostic  injection  of  tuberculin  a  dose  not 
larger  than  '01  c.mm.  and  the  fourth  and  last  dose  not  larger 
than  5  c.mm. 

The  high  diagnostic  value  of  tuberculin  injections  and  their 
absolute  safety  are,  according  to  the  observations  of  Binswanger 
[101],  most  marked  in  youth.  Of  261  children  whom  he  injected 
thirty-five  reacted,  and  of  the  total  number  forty-two  were 
examined  later  post-mortem.  Sixteen  who  had  reacted  were  all 
tubercular ;  of  twenty-six  who  had  failed  to  react,  twenty-five  were 
found  free  from  tubercle,  and  only  one  had  any  signs  of  tuber- 
culosis. The  latter  case,  moreover,  does  not  tell  against  the 
certainty  of  the  method,  as  the  injections  were  made  in  the  fifth 
week  of  life,  when  doubtless  infection  had  already  taken  place, 
but  no  tubercular  lesion  was  yet  present. 

Tuberculin  is,  then,  a  reagent  for  the  detection  of  tubercular 
disease,  not  for  tubercular  infection  without  anatomical  change. 
The  so-called  resistance  of  the  healthy  suckling  is  nothing  but 
the  expression  of  "  the  suckling's  freedom  from  tubercle  in  an 
anatomical  sense." 

Although  most  of  the  children  injected  by  Binswanger  were 
in  the  first  year  of  life,  not  one  of  the  thousand  individual  injec- 
tions led  to  any  bad  result.  It  would  be  unfair  to  demand  from 
a  diagnostic  method  greater  harmlessness  and  certainty  than  this. 
The  general  judgment  of  the  subcutaneous 

Conclusions.  test  can  be  summed  up  as  follows  :  After 
childhood,  it  is  the  sovereign  diagnostic 
method  and  renders  possible  the  early  diagnosis  of  tuberculosis 
in  all  its  localizations  and  forms.  Its  advantages  far  outweigh  its 
disadvantages ;  it  is  specially  valuable  in  view  of  its  diagnostic 
certainty.  It  is  applicable  to  ambulant  practice,  and  with  suffi- 
cient care  the   results  of   reactions  are  harmless.       All   harmful 


90  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

results  can  with  certainty  be  excluded  if  the  cases  are  properly 
selected,  indications  and  contra-indications  observed  and  a 
scrupulous  technique  employed. 

..      „  .  A     further     reduction     of     the     dose     of 

Needle-track  ■,  ,.  ,    ,        ,.  u-m,.q„ 

tuberculin    used   for   diagnosis   in    children 

Reaction  js    macje    m    t]ie    needle-track    reaction    of 

of  Escherich.        Escherich  [102]. 

This  is  nothing  else  than  an  allergic  test  of  the  subcutaneous 
tissue,  an  abbreviated  subcutaneous  test  occurring  with  a  small 
dose  of  tuberculin  and  not  leading  to  general  reaction. 

Reuschel   [103]    recommends  the  following 

The  Method.  procedure  :  a  dilution  of  old  tuberculin  is 
prepared  with  o'85  per  cent,  saline  which 
contains  o'5  c.mm.  of  tuberculin  in  1  c.c,  and  a  first  dose  of 
o'2  c.mm.  is  injected  on  the  inner  side  of  the  forearm.  In  prac- 
tice, therefore,  four  divisions  of  a  o'i  in  200  dilution  of  tuberculin 
are  used. 

If  the  reaction  is  positive,  inflammation  arises  in  the  sub- 
cutaneous tissue  and  is  projected  on  the  surface  of  the  skin  as  a 
sharply  circumscribed  red  spot,  quite  distinct  from  a  red  areola 
around  the  puncture,  which  is  not  characteristic.  Besides  the 
reddening,  there  is,  as  a  rule,  infiltration  due  to  oedema  and  great 
tenderness.  The  symptoms  generally  increase  in  the  first  twenty- 
four  hours,  reach  their  maximum  in  forty-eight,  and  begin  to 
pass  off  in  the  course  of  four  to  ten  days,  according  to  their 
intensity.  With  indistinct  reaction  and  no  general  disturbance 
the  dose  should  be  doubled. 

The  method  of  the  needle-track  reaction  fails,  according  to 
Reuschel,  in  cases  of  severe  cachexia,  and  generally  in  children 
with  miliary  tuberculosis.  But  it  affords  a  possibility  of  applying 
a  specific  test  to  children  in  spite  of  existing  fever  and  of  testing 
the  specific  import  of  temperature  oscillations  after  an  injection. 
Fever  without  needle-track  reaction  would  be  suspicious  of  non- 
specific origin. 

Finally,  the  reaction  makes  it  possible  to  control  the  results 
of  v.  Pirquet's  cutaneous  test  in  doubtful  cases.  Hamburger 
[104]  places  this  indication  in  the  front,  for  it  is  unsatisfactory 
that  in  cases  of  active  children's  tuberculosis  no  cutaneous  reaction 
should  take  place  and  thus  lead  the  diagnosis  astray.  In  such 
doubtful  cases  in  children  (when  from  clinical  examination  tuber- 
culosis is  suspected  and  the  cutaneous  test  is  negative)  then  the 
needle-track  reaction  should  be  tried  by  injecting  during  the 
next  two  or  three  days  o'i  to  ro  c.mm.  of  old  tuberculin.     If  a 


THE   SPECIFIC   DIAGNOSIS    OE  TUBERCULOSIS  Qi 

positive  needle-track  reaction  then  takes  place,  which  is  generally 
unaccompanied  by  any  severe  febrile  and  general  symptoms,  then 
it  may  be  assumed  with  certainty  that  there  is  a  tubercular  focus. 
According  to  Hamburger's  observations,  the  needle-track  reaction 
failed  so  very  seldom  in  cases  of  active  tuberculosis  in  children 
that  he  considers  it  the  best  of  all  the  tests  for  children. 

We  can  only  give  conditional  approval  of 
the    needle-track    reaction    as    a    means    of 

Escnencn  s  diagnosis  of  children's  tuberculosis.     It  is 

Reaction  Limited.  not  absolutely  trustworthy.  Moreover,  the 
dose  for  the  first  injection  proposed  by  Reuschel  (o"2  c.mm.) 
seems  to  us  too  high.  It  will  now  and  then  call  forth  violent 
general  reactions  with  high  fever,  which  may  become  serious  in 
the  case  of  children  already  febrile.  A  strict  contra-indication  to 
the  subcutaneous  injection  of  tuberculin  for  purposes  of  diagnosis 
is  given  by  fever.  And  this  must  be  adhered  to  under  all  cir- 
cumstances. We  must  therefore  warn  against  the  subcutaneous 
injection  of  Reuschel 's  proposed  dose  of  tuberculin  in  febrile 
children  for  the  purpose  of  observing  the  needle-track  reaction. 
Hamburger's  proposal,  too,  only  to  have  recourse  to  the  needle- 
track  reaction  after  the  cutaneous  inoculation  has  proved  negative, 
is  only  to  be  accepted  with  the  proviso  that  the  children  have  no 
fever.  Hamburger  himself  has  observed  that  tubercular  children 
will  sometimes  react  to  '001  c.mm.  of  tuberculin  and  even  to 
smaller  doses. 

For  the  rest,  both  in  children  and  in  adults  the  needle- 
track  reaction  may  be  useful  in  all  those  cases  where  the  subcu- 
taneous test  has  been  used,  so  far  as  the  appearance  and  condition 
of  the  site  of  inoculation  may  enhance  the  value  of  the  diagnosis. 
If  a  needle-track  reaction  takes  place  without  simultaneous  general 
reaction,  one  concludes  that  there  is  hypersusceptibility  of  the 
skin  to  tuberculin,  and  will  either  not  increase  at  all  or  only  very 
slightly  increase  the  next  diagnostic  dose  of  tuberculin.  If  the 
condition  of  the  site  of  injection  agrees  with  the  result  of  the 
general  tuberculin  reaction,  this  agreement  points  all  the  more 
certainly  to  the  presence  of  tuberculosis.  And  finally,  in  those 
cases  in  which  the  tuberculin  reaction  is  doubtful,  the  positive 
needle-track  reaction  may  be  able  to  turn  the  scale  and  to  cause 
us  to  refrain,  specially  in  the  case  of  children,  from  continuing 
the  injections  until  a  well-marked  tuberculin  reaction  occurs. 

With  adults  the  needle-track  reaction  by  itself  is  of  no  value 
for  diagnostic  purposes.  Injections  of  o"2 — I — 5  and  10  c.mm. 
of  tuberculin  may  lead  to  severe  needle-track  reactions,  without 
any  general  tuberculin  reaction  at  all.     With  adults  the  needle- 


92  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

track  reaction  is  evidently  too  severe,  much  more  so  than  the 
cutaneous  reaction.  On  the  other  hand  a  negative  needle-track 
reaction  with  simultaneous  increase  of  temperature  suggests  that 
the  fever  is  not  of  specific  origin  but  psychogenic  or  purposely 
simulated.     We  come  across  many  such  cases. 

So  in  dealing  with  children  the  needle-track  reaction  has  this 
importance — it  controls  or  confirms  a  negative  cutaneous  reaction 
in  the  case  of  tubercular  suspects.  In  this  respect  it  competes 
with'  the  intracutaneous  test,  which  should  always  be  preferred  in 
febrile  conditions. 

Besides,  the  needle-track  reaction  may  assist  in  interpreting 
the  results  of  the  subcutaneous  test  both  in  children  and  adults. 

Fever  is  a  contra-i indication  of  the  needle-track  reaction  both 
in  adults  and  especially  in  children. 

Tedeschi  recommends  the  lobe  of  the  ear  as  the  site  of  the  needle-track 
reaction.  We,  with  Montis,  reject  it,  because  this  "  auricular  reaction  " 
leads  to  disfigurement  and  sometimes  to  swelling  of  the  retro-auricular 
glands,  without  offering  any  special  advantage.  It  is,  at  the  least,  an 
unnecessary  measure  to  adopt. 


THE   SPECIFIC    DIAGNOSIS    OF   TUBERCULOSIS  93 


B. — Special  Section. 


Having  described  the  various  tuberculin  tests  and  their 
application,  we  come  now  to  the  special  features  which  may  in 
any  particular  case  lead  to  the  preference  of  one  or  another 
method  or  a  combination  of  several.  We  have  nowadays  the 
indisputable  advantage  of  not  being  limited  exclusively  to  the 
subcutaneous  method ;  by  the  discovery  of  the  local  tests  the  dia- 
gnostic method  has  been  extended  and  the  opportunity  given  for 
accurate  dosage  and  for  individualizing.  Of  this  advantage  we 
must  make  full  use,  but  it  must  not  be  forgotten  that  none  of  the 
tests  give  a  direct  proof  of  existing  tubercular  disease,  but  only 
prove  the  presence  of  a  specific  reactionary  body  which  pre- 
supposes the  existence  of  tubercle  toxin  in  the  body.  Therefore 
in  each  individual  case  from  the  result  of  the  test  in  combination 
with  the  clinical  facts  and  the  patient's  own  statements,  the 
doctor  has  to  devote  special  consideration  to  decide  where 
the  tubercular  focus  is  situated  in  the  body,  and  whether  it  is  a 
tubercular  infection  or  tubercular  disease.  The  following  section 
will  lay  down  the  lines  on  which  this  can  be  done. 

For  practical  convenience  the  methods  in  adults  will  first  be 
discussed  under  the  various  localizations,  and  then  a  special 
section  devoted  to  diagnosis  in  children. 

1.— TUBERCULIN   DIAGNOSIS  IN  TUBERCULOSIS  OF 

THE  LUNG. 

Pulmonary  tuberculosis  merits  detailed  discussion  on  account 
of  its  frequency  and  the  special  importance  and  difficulty  of  its 
early  diagnosis. 

Diagnosis  easy       The    clinical    Picture    of    well-marked    pul- 
monary    tuberculosis    is    practically   always 

in  well-marked  ,      ..,       ,   j.^     ,.  ,  J  .      ,  / 

and  without  difficulty  to  be  recognized  by 

physical    examination   and   furthermore,    in 

most  cases,  by  demonstration   of  tubercle  bacilli  in  the  sputum. 

But   if  the  clinical   history   is  uncertain   and   the  physical   signs 

doubtful,   or  if  the  history   indicates  phthisis  and  yet  the  signs 

are  negative,   the  question  whether  tubercular  disease  is  present 

or  not  is  difficult  to  decide.     Bacteriological   diagnosis  in   these 

cases  generally  fails  in  spite  of  the  modern  antiformin  method, 

either  because  there   is   no  secretion   from   the  lungs  or  because 

the  secretion  contains  no  tubercle  bacilli. 


94  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

_  ,  ,.  As  long;  as  tuberculosis  of  the  lung's  is  such 

a  universal  disease,  the  practitioner  will  be 

necessary  in  Doubt-  constantiy    meeting    such    cases,    and    will 

ful  Cases,  diagnose  them  wrongly  or  not  at  all,  if  the 

last,  the  best  and  the  keenest  diagnostic  agent,  the  injection  of 

tuberculin,  be  not  employed  and  its  result  considered  along  with 

clinical  observation. 

Manv    phvsicians,    it    is    true,    still    believe 
snn    to 

that    clinical    and    bacteriological    methods 

establish  an  Early    alone  are  sumcient)  j3Ut  surely  to-day  there 

Diagnosis  ;  are   ]-)Ut   few   hospital   doctors   who   do   not 

admit  the  special  value  of  tuberculin  diagnosis  in  the  early  stage 

of  pulmonary  tuberculosis.        In  any  case,   without  the  help   of 

tuberculin  it  must  repeatedly  happen  that  a  case  of  pulmonary 

tuberculosis  is  only  diagnosed  when  the  best  moment  to  effect  a 

certain,  rapid,  and  permanent  cure  is  past,  or  cases  are  treated  as 

tubercular    which    have    nothing    in    common    with    tuberculosis. 

Over  50  per  cent,  of  the  cases  sent  to  sanatoria  are  already  in 

the    second   and   third    stadium    of   pulmonary    tuberculosis    and 

5  to  8  per  cent,  are  not  tubercular  at  all  ! 

Trifling  physical  signs,  such  as  slight  retraction  of  one  apex, 

slight  alteration  of  percussion  note  at  one  or  both  apices,  slight 

flattening   of   the   chest   on    one   side,    indistinct   lagging,    slight 

weakening  or  roughening    of    the   inspiratory  murmur,    systolic 

cogwheel  breathing  (localized),   prolonged  expiration,   occasional 

inconstant  rhonchi,  or  constant  but  limited  to  a  spot  not  exactly 

at    the    apex — all    these    will    not    be    missed    by    the    practised 

observer,  but  will  often  not  suffice  to  establish  the  diagnosis  of 

commencing  pulmonary  tuberculosis. 

^  In     addition     there     are     not     infrequentlv 

to  confirm  ,.         r  r  .      .  , 

anomalies  of  structure  or  function  produc- 
Doubtful   Physical    ing.  differences  in  percussion  and  ausculta- 

S'gns.  tion    without    the    underlying    lung    being 

affected.  These  are  slight  scoliosis  in  the  cervical  or  dorsal 
region,  unilateral  muscular  hvpertrophy,  dropping  of  the  right 
shoulder,  differences  in  the  course  or  branching  of  the  upper 
bronchi,  &c. 

Examination  with  the  Rontgen  rays,  also,  in  many  cases  does 
not  remove  the  difficulties  of  diagnosis ;  catarrh  alone  is  certainly 
not  shown  ;  by  some  accident  or  other,  slight  thickenings  may  not 
be  shown  or  an  appearance  of  opaqueness  in  the  apex  may  simu- 
late the  beginnings  of  an  affection  of  the  lung.  As  to  whether 
shadows  denote  fresh  or  healed  infiltration,  calcareous  indura- 
tion, scars  or  puckered  nodules,  Rontgen-rav  examination  gives 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  95 

no  clue.  Even  the  Kreuzfuchs  improved  technique  with  the 
astral  screen  affords  no  certain  diagnostic,  much  less  differential 
diagnostic  aid  in  the  recognition  of  apical  changes ;  there  is  still 
no  agreement  as  to  the  striations  running  from  hilus  to  apex. 

So  there  are  doubts.  And  even  when  physical  examination 
and  the  use  of  the  Rontgen  rays  give  the  most  accurate  informa- 
tion as  to  the  site  and  extent  of  the  disease,  they  tell  us  nothing 
of  the  etiology  of  the  pulmonary  foci.  In  all  cases  where  tuber- 
culosis is  suspected,  specific  diagnosis  is  necessary,  so  that  timely 
treatment  may  be  commenced.  Here  we  entirely  agree  with 
Penzoldt  [105],  for  want  of  clearness  on  the  part  of  the  physician 
and  uncertainty  on  the  part  of  the  patient  are  much  more  fre- 
quently responsible  for  the  incurable  cases  than  the  latter's  neglect 
to  consult  the  doctor  in  time. 

The  grounds  which  formerly  prevented  the 

Universal  Applica-    medical  man  in  private  practice  from  using 

bility  of  the  tuberculin  in  diagnosis  are  done  away  with 

Method  ■  in  Private '  now   ^at    lt   *s   possible   to   use   tuberculin 

with  ease  and  safety.  Exceptions  apart, 
every  practitioner  should  now  be  in  a  position  to  test  any  doubtful 
case  with  tuberculin,  provided  he  is  successful  in  overcoming  any 
possible  opposition  on  the  part  of  the  patient  by  pointing  out  the 
safety  and  necessity  of  the  tuberculin  tests.  Then  also  in  private 
sanatoria,  the  advanced  stages  of  pulmonary  tuberculosis  will 
give  place  to  those  of  more  favourable  prognosis,   still  curable. 

In     hospital     practice     the     indication     for 
in      ospi  a   ,  tuberculin     diagnosis     is     present     for     all 

clinically  doubtful  cases.  The  decision  to  wait  until  the  physical 
signs  are  more  distinct  is  too  unscientific  from  the  physician's 
point  of  view  and  too  risky  for  the  patient.  The  salvation  of 
cases  of  pulmonary  tuberculosis  belonging  to  the  working  class 
is  the  earliest  possible  diagnosis.  And  as  our  public  hospitals 
are  in  duty  bound  to  diagnose  as  far  as  possible  all  cases  of  pul- 
monary tuberculosis  at  the  commencement  of  the  disease  and 
when  necessary  to  submit  them  to  an  expensive  course  of  treat- 
ment, tuberculin  diagnosis  has  become  an  integral  part  of  the 
equipment  of  the  hospital  physician. 

.  And   lastly,    in   sanatoria   it   is  a   necessary 

in  Sanatorium.       part  of  thdr  activity  to  make  certain  of  the 

diagnosis  in  view  of  the  many  attacks  on  their  results.  The 
opponents  of  sanatoria  will  be  robbed  of  one  of  their  most  potent 
weapons  when  it  is  proved  beyond  question  that  the  lung  affec- 
tions of  sanatorium  patients  are,  in  actual  fact,  of  a  tubercular 
nature, 


96  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

And  further,  however  scrupulous  the  cleanliness  and  the 
observation  of  rules  for  coughing  and  spitting  in  the  sanatorium, 
there  is,  in  view  of  the  indisputable  correctness  of  the  theory 
of  spray  infection,  an  increased  risk  in  prolonged  and  intimate 
relation  with  tubercular  subjects  for  those  with  unsound  lungs 
specially  susceptible  to  tubercle  bacilli.  Hence  the  exclusion  of 
the  non-tubercular  from  the  sanatorium  must  be  insisted  on. 

Furthermore,  the  not  inconsiderable  cost  of  treatment  in  a 
sanatorium  forbids  making  it  accessible  to  those  in  whom  no 
tubercular  disease  is  present  and  in  whom  life  and  the  ability 
to  work  are  not  threatened.  At  the  least  it  would  be  a  hardship 
to  withdraw  a  non-tubercular  case  for  three  months  or  more  from 
his  familv  and  occupation.  Hence  therapeutic,  practical, 
hygienic  and  social  grounds  all  combine  to  make  the  employ- 
ment of  tuberculin  diagnosis  essential  in  the  sanatorium.  The 
armoury  of  diagnostic  weapons  is  incomplete  without  it,  as  it  will 
confirm  or  exclude  a  clinically  doubtful  case  of  pulmonary  tuber- 
culosis. That  in  many  initial  cases  a  verv  careful  clinical 
examination  alone  suffices  will  not  be  disputed.  But  in  just  as 
many  cases  this  alone  is  insufficient,  certainlv  in  the  material 
sent  to  the  sanatoria  without  characteristic  clinical  symptoms  and 
without  medical  reports.  We  will  only  mention  the  badlv- 
nourished  and  narrow-chested  men,  who  are  medically  excluded 
from  military  service,  and  the  anaemic  and  chlorotic  girls  who 
largely  fill  our  women's  sanatoria.  Malnutrition,  chlorosis,  &c, 
may  be  at  the  root  of  latent  tuberculosis;  but  at  any  rate  as 
frequently  it  has  no  connection  with  it.  These  may  be  all 
suspected  of  tuberculosis,  but  it  is  often  left  to  the  sanatorium  to 
decide  whether  they  are  cases  of  active  pulmonary  disease  needing 
treatment. 

Obiection  that       ^ne    ODJection     is    raised    that    tuberculin 

-.       ,.  .  diagnosis  eaves  no  certainty  as  to  the  seat 

Reaction  gives  no      r  ,,      ,  ,b       ,       ,  .  J    .      ,  , 

of    the    tubercular    focus    in    the    lung    and 

does  not  distinguish  in  adults  between 
bite  ot  Disease,  active  and  inactive  disease.  This  is  justi- 
fied where  one  is  limited  to  the  local  tests;  but  it  neglects  the 
fact  that  although  alone  the  subcutaneous  test  does  not  avail 
much,  yet  in  combination  with  other  means  of  early  diagnosis 
it  is  of  the  greatest  assistance  in  the  certain  and  early  recognition 
of  active  pulmonary  tuberculosis. 

-r.       ■-       i  The    subcutaneous    tuberculin    reaction    in 

The  Focal  p  .    . 

cases  ot  pulmonary  tuberculosis  is  generally 

accompanied  by  symptoms  which  show  the 

lung  to  be  the  seat  of  disease.     The  frequent  spontaneous  com- 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  97 

plaints  of  dragging,  stretching,  or  shooting  pains  in  the  chest 
and  increased  irritation  and  cough  are  often  confirmed  by  the 
appearance  or  increase  of  sputum.  As  early  as  1890,  Robert 
Koch  described  the  "  increased  cough  and  sputum  after  the  first 
injections"  as  a  "local  reaction"  and  assumed  that  similar 
changes  occur  in  the  lungs  as  are  directly  observed  in  lupus. 
To-day  we  can  prove  the  occurrence  of  these  "local"  reactions 
in  tubercular  lungs  (focal  reactions),  although  their  intensity  does 
not  always  reach  any  definite  point. 

The  focal   reaction   consists  of  the  appear- 
Its  Nature.  ance   or   increase   of   physical   signs  :    rales 

occur,  or  where  these  were  present  before 

become  clearer  or  more  frequent;   well-marked  alteration   in  the 

breath  sound  over   the  affected   spot   in   the   sense   of   impurity; 

jerkiness,  roughness,  or  sharpness ;  diminished  resonance  becomes 

more  marked  or  extends ;   localized   pleuritic   symptoms   become 

plainer. 

In   consequence   of  the   focal   reaction   the   demonstration   of 

tubercle  bacilli  may  be  made  possible,  as  in  the  case  illustrated 

by  Chart  8.     This  has  previously  only  seldom  been  done ;  with  the 

help  of  the  antiformin  method  it  now  succeeds  more  frequently. 

_  .  As  to  the  frequency  of  a  physically  demon- 

Demonstration  t  1       r        1  *.-  4-U       1       ~„      ~~~~f 

strable    focal    reaction    in   the    lungs,    exact 

of  Focal  estimates  have  been  furnished  by  Kammerer 

Reaction.  [106],  Otten  [107],  v.  Romberg  [108]  from 

the  Tubingen   Medical   Clinic,   and  by  Walterhofer   [109]    from 

the  Wilhelmsheim  Sanatoria. 

Of  324  patients  in  the  Tubingen  Clinic  who,  between  October  igo4  and 
October  igog,  received  subcutaneous  tuberculin  on  account  of  suspected  apical 
changes,  igy  (=6o"8  per  cent.)  gave  an  apical  focal  reaction  and  also  a 
general  reaction,  24  (  =  7'4  per  cent.)  a  focal  reaction  without  simultaneous 
general  reaction,  76  (23' 5  per  cent.)  a  general  reaction  only,  and  27  (  =  8"  3 
per  cent.)  neither  focal  nor  general  reaction.  In  three-quarters  of  the  cases 
the  apical  reaction  took  the  form  of  the  occurrence  or  increase  of  dulness ; 
only  in  one  quarter  was  it  exclusively  an  auscultatory  phenomenon.  In 
less  than  half  the  cases  was  the  increase  of  the  percussion  signs  accompanied 
by  fresh  or  increased  rales  or  the  like. 

In  the  Wilhelmsheim  Sanatoria  156  suspected  cases  were  tested;  of 
these  46  were  proved  neither  tubercular  nor  needing  treatment.  Of  the 
remaining,  no  proved  to  have  active  disease,  60  (=  54" 5  per  cent.)  gave  a. 
focal  reaction,  of  which  55  were  proved  by  auscultation  and  5  by  percussion. 
The  auscultation  signs  consisted  in  48  cases  of  crepitation  rales,  and  in  7  of 
pronounced  changes  in  the  breath-sound. 

It  is  also  of  interest  that  of  the  ig7  cases  in  the  Tubingen  Clinic  which 
gave  neither  focal  nor  general  reaction,  118  reacted  to  a  tuberculin  dose  up 
to  2   c.mm.,   63  only   to    5    c.mm.,   and   no   less   than    16   required   a   dose   of 


98  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

10  c.mm.  to  call  forth  a  focal  reaction.  This  last  fact  is  important  with 
regard  to  the  attitude  to  be  adopted  towards  the  question  of  the  maximal 
test  dose. 


Recognition 
of  the 


The  focal  reaction  is  usually  demonstrable 
for  two  to   three  days;   the  physical  signs 
seldom  last  up  to  four  or  five  days.     Very 
Focal   Reaction.      gentle    percussion    and    very    careful    and 
repeated  auscultation  are  necessary  for  its  recognition. 

The  conditions  here  are  no  different  from  those  in  chest  examination  in 
general.  Even  sanatorium  doctors  do  not  agree  as  to  which  of  the  methods 
— percussion  or  auscultation — deserves  recognition  as  the  more  important 
for  diagnosis.  This  difference  of  opinion  must  also  find  expression  in 
examining  the  chest  for  the  presence  or  absence  of  a  focal  reaction.  There 
fore  it  is  not  remarkable  that  in  the  Tubingen  Clinic  a  preponderance  of 
percussion  phenomena  and  in  the  Wilhelmsheim  Sanatoria  of  auscultation 
signs  has  been  recorded.  Our  own  experiences  coincide  with  those  of 
Waltershofer,  that  the  proof  of  a  focal  reaction  by  percussion  is  attended 
with  greater  difficulties  and  that  it  is  more  frequently  and  certainly  demon- 
strable by  auscultation,  especially  by  the  occurrence  of  crepitation  rales. 
We  should  like,  without  at  present  being  able  to  give  percentage  figures, 
to  impress  the  fact  that  in  the  majority  of  cases  there  are  simultaneous  sub- 
jective symptoms  and  objective  percussion  and  auscultation  signs  which 
refer  the  site  of  the  reaction  to  the  apices  of  the  lungs,  the  pleura,  the 
tracheo-bronchial  glands,  and  so  on.  At  any  rate,  both  methods  are  neces- 
sary to  determine  whether  changes  in  the  lung  have  or  have  not  taken  place 
in  a  clinically  doubtful  case  and  so  to  give  a  positive  or  negative  diagnosis. 

No   injury  to  the  organism   has  ever  been. 
Safety.  noticed,  nor  has  the  condition  of  the  lungs 

been  made  worse  by  the  focal  reaction. 
v.  Romberg  and  Olten  point  this  out  expressly,  and  we  wish  to 
confirm  it  from  a  still  wider  experience  in  order  to  meet  the  objec- 
tion that  it  is  dangerous  to  use  the  subcutaneous  test  just  because 
of  the  focal  reaction  in  the  lungs. 

-  ,        .  f       The  great  advantage  of  an  apparent  focal 

/\ci vantages  ot  ,       .      ,  . 

_       ,   _         .  reaction  is  that  it  shows  the  active  character 

Focal   Reaction.        r  ,1  ,  .   u        <        ,.  T1t7. 

ot   the  pulmonary  tubercular  disease.     We 

have,  therefore,  from  the  beginning  preferred  the  subcutaneous 
tuberculin  diagnosis  to  the  local  tests,  and  now  find  ample  confir- 
mation of  our  point  of  view  in  the  above-mentioned  facts  published 
by  the  Tubingen  Medical  Clinic. 

Further  reports  from  this  source,  made  on  a  average  two  and  a  half 
years  later,  showed  that  of  eighteen  individuals  who  showed  neither  a 
general  nor  a  focal  reaction  and  underwent  no  treatment,  seventeen 
remained  permanently  healthy  and  fit  for  work,  and  only  one  two  years 
later  was  taken  ill  with  fistula  of  the  anus  and  tuberculosis  of  the  larynx. 


THE    SPECIFIC    DIAGNOSIS    OF   TUBERCULOSIS  99 

.Out  of  forty-seven  examined  later  who  had  only  given  a  general 
reaction,  forty-four  were  found  to  be  healthy  and  fit  for  work,  although 
only  two  had  taken  a  course  of  treatment  at  the  sanatorium.  Three  showed 
a  deterioration  in  the  condition  of  the  lungs  and  in  the  general  well-being. 

On  the  other  hand,  the  subsequent  examination  of  135  individuals  who 
had  given  a  focal  reaction  gave  much  less  favourable  results,  although 
those  examined  had  with  one  exception  spent  a  long  time  in  a  sanatorium. 
Two  had  died,  eighty-two  cases  had  to  be  pronounced  worse,  and  only 
fifty-one  were  permanently  fit  for  work  and  showed  a  favourable  inactive 
condition  of  the  lungs.  And  here  it  was  noticed  that  the  number  of  those 
who  had  improved  was  relatively  much  higher  among  the  private  patients 
than  among  the  poorer  sanatorium  patients. 

_       .   _,       ,.  The   result   of   these   subsequent    investjVa- 

Focal  Reaction  .  ,  \u  n     -* 

tions   is   very    noteworthy.        Above   all,    it 

indicates  points  to  the  great  difference  in  the  course 

Active  Disease.  0f  ^g  a.pica.1  disease  between  those  cases 
with  focal  reaction  and  fhose  with  general  reaction,  without  focal 
symptoms.  In  the  first  category,  in  spite  of  treatment  in  sana- 
toria, nearly  three-fifths  were  found  to  be  in  a  worse  condition, 
only  two-fifths  stationary  and  fit  for  work,  but  on  the  other  hand 
those  in  the  second  category  were  all,  with  few  exceptions,  and 
without  a  course  of  treatment,  in  an  unchanged  condition.  From 
these  facts  we  must  conclude  that  focal  reaction  in  the  apices 
definitely  indicates  fresh  active  pulmonary  tuberculosis,  while  the 
general  reaction  only  permits  us  to  infer  that  there  is  an  infection 
somewhere  or  other  in  the  body.  This  enormously  increases  the 
importance  of  the  subcutaneous  tuberculin  test  in  the  early 
diagnosis  of  pulmonary  tuberculosis.  And  it  is  quite  an  unjustifi- 
able depreciation  of  the  value  of  tuberculin  diagnosis  if  the  general 
reaction  alone  is  selected  from  the  complex  of  its  reactive 
phenomena  and  identified  with  v.  Pirquet's  test  in  adults  in 
diagnostic  significance.  For  even  this  is  not  correct.  We  call 
to  mind  numerous  observations  when  adults,  clinically  tubercular 
suspects,  reacted  promptly  or  late,  slightly  or  severely  to  the 
cutaneous  test,  but  who  displayed  no  sign  of  general  or  febrile 
reaction  to  subsequent  diagnostic  injections.  In  these  cases  the 
positive  cutaneous  reaction  signified  the  presence  of  tubercular 
infection,  the  negative  subcutaneous  test  the  absence  of  tubercular 
disease. 

We  must  make  use  of  it  in  apical  changes,  the  etiologv  and 
activity  of  which  is  doubtful,  so  as  to  be  able  to  note  the  appear- 
ance or  absence  of  the  focal  reaction,  and  thereby  select  the  course 
of  treatment.  W  nether  special  treatment  is  indicated  or  not  in 
individual  cases  for  those  patients  who  onlv  give  a  general  reaction 
to  subcutaneous  tuberculin  will  depend  on  the  history,  the  general 


IOO  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

condition,  other  clinical  observations,  &c.  Treatment  is  neces- 
sary for  those  cases  which  react  generally  and  locally  when  the 
focal  reaction  has  been  demonstrated. 

_^  ,  ..  Tuberculin   diagnosis   is   of   special  import- 

Tubsrculin  .  . 

ance    where    suspicion    of    tuberculosis    is 

Diagnosis  in  present    in   pregnant   and   lying-in    women. 

Pregnancy.  Whether    treatment    must    be    commenced 

during  pregnancy,   whether  special  measures  must  be  taken   for 

the  confinement  (induction  of  labour),  whether  suckling  is  to  be 

allowed,  are  questions  of  such  urgent  importance  to  mother  and 

child  that  the  diagnosis  must  not  only  be  made  in  good  time,  but 

with    certainty.       An    unfavourable    influence    of    the    diagnostic 

injection  on  these  patients  has  not  been  observed.     Labour  pains 

have  never  resulted  nor  has  the  child  been  harmed. 

_._         ,.   .  The   second   indication    for   tuberculin   dia- 

Difterential  .     .  ,  ,.„,     ti     . 

gnosis  is  the  occurrence  ol  difficulty  in  mter- 

agnosis.  preting  a  disease  which  is  certainly  present. 

The  question  mav  arise  whether  tuberculosis  of  the  lung  is 
present,  or  carcinoma,  or  sarcoma,  which  may  also  give  rise  to' 
haemoptysis  and  impaired  percussion,  even  at  the  apices,  or 
whether  the  condition  is  one  of  infiltration  due  to  echinococcus, 
or  of  actinomycosis,  or  of  syphilis,  which  may  all  occur  with 
haemoptysis,  wasting,  and  night-sweats.  In  the  latter  case  care 
is  necessarv  in  the  interpretation  of  the  tuberculin  reaction, 
as  local  and  general  reactions  have  been  said  to  occur  with  car- 
cinoma, syphilis,  and  echinococcus.  This  is  clearly  because  in 
addition  to  the  carcinoma  or  syphilis  which  are  the  chief  feature 
in  the  clinical  picture,  tubercular  foci  are  also  present  in  the  body. 
Therefore  a  negative  result  of  the  test  is  the  more  valuable.  As 
an  example  we  have  given  the  case  of  a  patient  with  unilateral 
dulness  of  the  upper  lobe  and  blood-stained  purulent  sputum 
containing  no  tubercle  bacilli ;  he  failed  to  react  in  any  way  to 
tuberculin  and  was  suffering  from  carcinoma  of  the  liver  and 
metastasis  in  the  lung.  The  course  of  the  disease  pointed  to  a 
malignant,  the  haemoptysis  to  a  progressive  process ;  if  this  had 
been  of  a  tubercular  nature,  a  reaction  would  certainly  have 
occurred  to  subcutaneous  tuberculin  doses  of  i — 10  c.mm.  (Chart 
No.  n). 

More  frequently  in  the  case  of  areas  of  dulness,  catarrhal 
signs  or  thickenings  of  the  pleura  will  it  be  necessary  to  decide 
between  pulmonary  tuberculosis  and  simple  koniosis,  bronchitis, 
bronchiectasis,  rheumatic  or  traumatic  pleurisy,  &c.  Besides 
these  Kronig  [no]  has  recently  called  attention  to  collapse 
induration  of  the  right  apex  due  to  obstructed  nasal  breathing, 


THE    SPECIFIC  DIAGNOSIS    OF    TUBERCULOSIS  IOI 

simulating  on  physical  examination  right  apical  disease,  although 
etiologically  having  nothing  whatever  to  do  with  tubercle.  These 
various  conditions  together  are  not  very  infrequent,  a  fact  shown 
by  the  annual  reports  of  the  sanatoria  and  by  the  observations  of 
Bliimel  [in]  and  ourselves.  But  we  must  leave  it  undecided 
whether  many  of  these  signs  are  not  due  to  a  quite  obsolete, 
shrunken  and  healed  tubercular  apical  process.  Tuberculin  will 
in  such  cases  lead  to  the  diagnosis  being  made,  but  only  when 
taken  in  conjunction  with  clinical  methods;  from  the  divorce  of 
the  two  we  cannot  too  strongly  warn. 

With    the    recognition    of    the    special    dia- 
Safety.  gnostic  value  of  the  subcutaneous  tuberculin 

test,  a  doubt  has  been  expressed  as  to  whether  patients  suffering 
from  pulmonary  tuberculosis  may  be  injured  by  the  rapid  increase 
in  the  doses  of  tuberculin  until  the  focal  reaction  takes  place. 
Especially  the  question  has  been  asked  whether  sometimes  the 
general  and  focal  reactions  are  not  too  severe  and  may  not  rouse 
into  activity  old,  inactive  disease  of  the  apex  of  the  lung.  One 
can  hardly  concede  even  the  possibility  of  such  a  thing.  For 
truly  healed  apical  foci  will  not  become  the  site  of  a  focal  reaction 
and  active  processes  in  the  lungs  do  not  suffer  any  injury 
according  to  our  many  years'  experience.  In  the  very  rare 
observations  to  the  contrary  the  question  whether  they  are  post 
hoc  or  propter  hoc  does  not  seem  to  us  to  be  conclusively  answered. 
In  any  case,  we  must  at  least  agree  with  Penzoldt's  [105]  stand- 
point at  the  Congress  on  Internal  Medicine  (1910)  :  "With  the 
exercise  of  the  greatest  precaution,  ill-effects  have  been  so 
very  seldom  observed  in  thousands  of  tests  that  they  may  be 
considered  as  negligible."  By  precaution  must  be  understood 
attention  to  the  technique,  the  indications  and  contra-indications. 

.    m}  Ulrici   [112]  has  recently  reported  that  he  has  per- 

UlriCI  S    Criticism      forme(j   the   subcutaneous  test  on   120  patients,   and 

of  the  that    "  amongst    the     106    general    reactions    there 

S.        .  were,     in     addition     to     seventeen     severe     febrile 

ubcutaneous  '.  ,  ,        ■   , 

reactions,  nine   cases    showing   exquisite   harm   due 
Method.  to    the   tuberculin,    although    this    was    fortunately 

only  temporary/'  The  severe  febrile  reactions  consisted  of  temperatures  of 
39°  to  400  C.  and  over,  "  which  is,  at  any  rate,  very  unpleasant  for  the 
patient."  This  must  be  admitted,  and  shows  that  the  subcutaneous  test 
must  not  be  performed  experimenti  causa,  but  is  limited  by  definite  indica- 
tions and  contra-indications.  But  when,  in  another  part  of  the  same  speech, 
Ulrici  states  that  he  has  given  test  tuberculin  injections  to  "  thirty-six 
patients  with  pulmonary  tuberculosis  in  the  first  to  the  third  stadium,"  and 
has  brought  about  more  or  less  severe  fever,  such  tuberculin  diagnosis  is 
of  course  quite  indefensible. 

In  addition,  Ulrici  has  observed  the  following  i-  serious  results":      (1) 


102  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

Four  weeks'  duration  of  subfebrile  temperature  in  two  cases.  (2)  In  one 
case,  lytic  fall  of  fever  from  400  C.  only  after  seven  days.  (3)  In  three  cases, 
particularly  severe  malaise  and  serious  objective  condition  after  the 
injection.  (4)  In  one  patient  very  severe  febrile  intestinal  catarrh  which 
occurred  simultaneously  with  the  reaction  and  persisted  for  fourteen  days. 
(5)  A  case  of  acute  serous  otitis  occurring  with  the  reaction  which  was 
treated  for  three  weeks  before  a  cure  was  effected.  (6)  In  one  patient, 
complete  paresis  of  the  sphincter  vesicae,  which  gradually  disappeared  in 
three  weeks.  Finally,  Ulrici  claims  that  a  positive  tuberculin  reaction  not 
infrequently  causes  a  fairly  severe  psychical  shock  which  may  have  disas- 
trous results.  The  possibility  of  such  considerable  bodily  and  psychical 
damage  caused  by  a  positive  reaction  is  considered  by  him  one  of  the  many 
reasons  for  the  rejection  of  the  subcutaneous  test  in  ambulant  practice. 

In  reply  to  this,  we  must  state  that  during  the  last  ten  years  we  have 
made  at  least  10,000  to  12,000  subcutaneous  injections  in  upwards  of  4,000 
tubercular  suspects.  In  both  males  and  females  we  have  observed  some 
1,000  high  febrile  reactions  which  at  their  height  were  more  or  less 
unpleasant  and  troublesome,  but  in  two,  three,  or  at  the  most  four  days, 
generally  gave  place  to  a  feeling  of  increased  well-being.  Presuming  that 
the  tuberculin  injections  for  diagnosis  are  indicated  and  not  given  without 
choice  or  consideration,  these  phenomena  of  the  specific  diagnosis,  even  in 
tuberculosis  of  the  third  stadium,  are  such  as  every  doctor  can  make  himself 
responsible  for,  and  will  not  be  regarded  or  described  by  his  patients  as 
"  harm."  Further,  amongst  about  4,000  tuberculin  reactions  we  have  never 
observed  a  single  one  which  entailed  a  week's  fever,  nor  severe  febrile 
intestinal  catarrh,  nor  acute  inflammation  of  the  middle  ear,  nor  any 
paralysis  of  the  sphincter  vesicas.  But  we  can  record  that  of  three  patients 
in  whom  the  test  injection  was  not  made  for  purely  external  reasons,  there 
took  place  at  the  intended  time  of  injection  in  one  acute  suppuration  of  the 
middle  ear  spreading  to  the  labyrinth  and  subsequent  chronic  ill-health,  in 
another  tubercular  meningitis  developed,  and  the  third  was  found  dead  in 
his  bed  on  the  morning  following  the  day  when  the  injection  should  have 
been  made  without  the  cause  of  death  being  definitely  decided.  We  must 
leave  it  open  to  the  judgment  and  common-sense  of  the  reader  whether  he 
will  accept  the  alarming  accumulation  of  "  exquisite  harm  caused  by  tuber- 
culin "  which  Ulrici  has  observed  in  but  106  reactions,  or  whether  he  will 
share  our  opinion  of  the  harmlessness  of  diagnostic  injections  applied  lege 
artis,  which  is  held  by  Penzoldt,  F.  Kraus,  and  others  and  is  based  on  some 
thousands  of  personal  observations. 

Psychic  shock  with  serious  results  caused  by  a  positive  reaction  has 
never  been  observed  in  our  daily  intercourse  with  reacting  patients,  not 
even  amongst  a  large  number  of  female  patients.  Therefore,  on  this  score 
again,  we  cannot  advise  abstention  from  the  method,  leaving  the  patient 
doubtful  as  to  his  disease  or  giving  him  a  faulty  diagnosis. 

What  form,  then,  does  the  method  of  tuber- 
culin diagnosis  take  in  practice  when  tuber- 
culosis of  the  lung  is  suspected?  In  the  first  place,  the  local 
methods  of  reaction,  i.e.,  the  cutaneous,  percutaneous,  and  con- 
junctival tests,  are  to  be  employed,  and  they  alone  in  all  cases 
where  the  subcutaneous  method  is  contra-indicated ;  when   fever 


THE    SPECIFIC   DIAGNOSIS    OF    TUBERCULOSIS  IO3 

is  present  or  haemoptysis  has  recently  occurred,  in  cases  of  cardiac 
and  renal  disease,  of  epilepsy,  hysteria,  and  severe  neurasthenia, 
in.  cases  where  intestinal  or  miliary  tuberculosis  is  suspected,  in 
individuals  recovering  from  acute  disease  or  otherwise  in  a  feeble 
state  of  health,  in  all  cases  of  severe  diabetes,  tendency  to 
apoplexy,  advanced  arteriosclerosis  and  amyloid  degeneration  of 
the  abdominal  viscera. 

In  any  particular  case  it  must  be  borne  in 
Cutaneous  mjnd   that    -n   adults    the   CLltaneous   test- 

iest, which  is  to  be  preferred  to  the  percutaneous 

— is  also  positive  in  the  case  of  foci  in  lung  and  bronchial  gland 
so  inactive  as  to  no  longer  deserve  the  name  of  disease.  In 
adults,  then,  a  positive  cutaneous  reaction  points  only  to  a  tuber- 
cular infection  having  some  time  occurred,  whereas  a  negative 
reaction  excludes  with  great  probability  the  presence  of  tubercle 
in  the  body  and  hence  also  in  the  lung.  We  cannot  confirm 
K6gel' s  [113]  statement  that  a  deferred  and  often  slight  cutaneous 
reaction  is  characteristic  of  fibrous  tubercular  processes  without 
tubercle  bacilli  in  the  sputum  ;  on  the  contrary,  we  have  usually 
observed  prompt  and  severe  cutaneous  reactions  in  this  form  of 
the  disease. 

_  .  The   conjunctival  application   of   tuberculin 

Conjunctival  .  \    ,         ,  .   u         i     • 

J  in    suspected    pulmonary    tuberculosis    is    a 

priori  limited  to  individuals  with  sound 
eyes.  This  greatly  restricts  its  field  of  usefulness;  and  there  is 
yet  a  further  restriction.  According  to  our  comparative  investi- 
gations [59],  a  single  instillation  is  quite  insufficient  for  purposes 
of  diagnosis;  the  same  applies  also  to  repetition  with  4  per  cent, 
dilution  in  the  same  or  the  other  eye.  Of  the  early  cases  of 
pulmonary  tuberculosis,  just  those  in  which  the  method  is  in- 
dicated, only  every  alternate  case  reacts  to  a  second  instillation. 
Tuberculosis  can  with  certainty  be  excluded  only  after  fourfold 
repetition  on  the  same  eye  has  occasioned  no  reaction.  Hence  in 
those  persons  in  whom  the  first  two  instillations  remain  negative, 
the  absence  of  pulmonary  tuberculosis  may  not  be  assumed ;  in 
at  least  50  per  cent,  of  cases,  this  would  involve  an  error  with 
far-reaching  consequences. 

1-  11     .         r  We  must  state  that  the  conjunctival  test  is 

Fallacies  of  ,  .    ,  ,  ,.  ,  ,      ,  ,       ,• 

,        _      .  highly    unreliable    tor    early    diagnosis  :    it 

the   Conjunctival  (  m     •     .      ,         -.  •  ,  •"        .      .     •     .1 

J  tails  just  where  it  is  most  important — in  the 

es  •  initial     stage    of     pulmonarv     tuberculosis. 

With  advancing  disease  the  conjunctival  reaction  becomes  more 

trustworthy;  in  Stadium  II  (Turban),  75  per  cent    of  cases  react 

to  two  instillations,  in  Stadium  III  100  per  cent    even;  exception 


I04  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

must  be  made  for  the  final  stages  and  for  cachectic  patients  who 
do  not  react  at  all.  Thus  the  conjunctival  reaction  is  not  the 
reaction  of  initial  pulmonary  tuberculosis,  but  of  the  advanced 
open  stages  with  bacilli  in  the  sputum.  But  for  pulmonary 
tuberculosis  of  Stadium  II  and  III,  tuberculin  diagnosis  is 
unnecessary.  If  the  conjunctival  reaction  is  positive,  this  justifies 
no  conclusion  as  to  the  site  of  the  tubercular  focus  in  the  lung, 
its  active  or  inactive  character  or  the  prognosis.  Wolff-Eisner's 
view  that  the  conjunctival  reaction  is  the  reaction  of  active  pul- 
monary tuberculosis  seems  quite  incorrect. 

„  .  From   all   this   it   will   be  seen   that   in    the 

Insufficiency  ,       ,.  ,   ,.        ,  .   u 

'  early   diagnosis   or   adult   pulmonary   tuber- 

culosis   no   crucial   significance   can   be  ad- 
Local    Tests.  mitted     for     the     local     reaction  methods. 
Especially   in   pregnancy  and   confinement,    their   significance   is 
influenced  by  processes  dependent   on   these   conditions,    not   on 
tuberculosis. 

In  the  institution,  cutaneous  and  conjunctival  tests  may  be 
used  either  separately  or  simultaneously  prior  to  the  subcutaneous 
test.  But  their  disadvantages  must  not  be  lost  sight  of, 
especially  their  uncertainty.  If  both  cutaneous  and  conjunctival 
tests  are  positive,  then  tuberculosis  may  be  decided  upon  without 
any  indication  of  its  site  or  character.  If  one  or  both  are  negative, 
the  absence  of  a  tubercular  focus  is  not  demonstrated.  On  the 
contrary,  it  must  again  be  emphasized  that  both  methods  may 
fail  in  spite  of  active,  even  open  pulmonary  tuberculosis  being- 
present. 

_,   ,  In  all  these  cases  the  subcutaneous  method 

Subcutaneous        ,  ..  ...         , 

_  has    finallv    to    decide    whether    tubercular 

Test 

disease  is  present  or  not.     If  the  cutaneous 

test  is  positive,  but  the  subcutaneous  negative,  then  it  is  certain 
that  there  is  no  active  pulmonary  tuberculosis  and  the  supposition 
that  there  is  an  obsolete,  healed,  or  inactive  focus  is  justified. 
Such  cases  are  constantly  diagnosed  by  us  and  are  not  admitted 
for  sanatorium  treatment.  The  subcutaneous  tuberculin  method 
is  therefore  not  so  sharp  and  sensitive  as  the  cutaneous  reaction. 
Nevertheless,  the  question  must  be  raised — of  great  import- 
ance in  general  practice — whether  every  patient  who  reacts  to  the 
subcutaneous  injection  is  suffering  from  active  tuberculosis  and 
therefore  requires  treatment.  In  consideration  of  the  facts  estab- 
lished by  Franz,  Kammerer,  Otten,  and  v.  Romberg,  and  already 
mentioned  earlier,  we  must  answer  this  question  in  the  negative. 
Among  those  who  give  a  reaction,  a  selection  has  to  be  made  of 
those  who  require  treatment.     Only  those  will  be  looked  upon  as 


THE    SPECIFIC   DIAGNOSIS    OF    TUBERCULOSIS  IO5 

tubercular  patients  requiring  treatment  who  either,  with  good 
general  condition,  give  a  focal  reaction  after  subcutaneous  in- 
jection, or  who,  without  any  demonstrable  focal  reaction  have 
an  undoubtedly  positive  clinical  history  characteristic  of  the 
initial  stages  of  pulmonary  tuberculosis  (cough,  sputum,  loss  of 
weight,  night  sweats)  combined  with  a  condition  of  the  lungs 
which  gives  rise  to  more  or  less  suspicion  of  tuberculosis.  There- 
fore what  we  have  said  for  years  and  wish  once  more  to  emphasize 
here,  still  holds  good  :  The  subcutaneous  tuberculin  reaction  by 
itself  and  apart  from  all  clinical  methods  of  examination,  only 
indicates,  as  a  rule,  that  tuberculosis  is  present,  but  in  conjunction 
with  clinical  history,  inspection,  percussion,  and  auscultation 
(focal  reaction),  it  is  still  to-day  the  supreme  aid  to  the 
diagnosis  of  the  active  initial  stage  of  pulmonary  tuberculosis  in 
adults. 

The   tuberculin    reaction    is   also   of   use   in 
the   prognosis   of   tuberculosis.      Especially 
Prognosis.  -m     pUimonarv     tuberculosis     the     clinical 

methods  are  not  reliable  enough  and  for  the  most  part  are  in- 
sufficient for  the  prognosis.  Moreover,  eleven-twelfths  of  all 
deaths  from  tuberculosis  are  the  result  of  pulmonary  tuberculosis, 
and  only  one-twelfth  from  other  forms  of  tuberculosis,  so  that 
it  would  seem  well  here  to  discuss  the  question  of  the  prognostic 
importance  of  the  tuberculin  reactions. 

The  cutaneous  reaction  tells  us  nothing  as  to  the  prognosis 
of  patients  suffering  from  pulmonary  tuberculosis,  for  it  only 
indicates  that  somewhen  and  somewhere  the  organism  in  question 
has  been  infected  with  tubercle  bacilli.  So  that  the  cutaneous 
reaction  of  v.  Pirquet  is  a  somewhat  rough  method  of  diagnosis 
and  by  no  means  a  help  in  prognosis.  The  suggestion,  too,  that 
a  deferred  cutaneous  reaction  is  a  good  criterion  for  prognosis, 
and  that  a  rapid  reaction  in  a  manifest  case  of  tuberculosis  is  an 
unfavourable  prognosis,  is  more  a  matter  of  speculation  than  fact. 
Only  this  much  seems  proved — when  phthisical  patients  do  not 
react  at  all  to  the  cutaneous  test  the  prognosis  is  unfavourable, 
and  that  with  a  more  severe  cutaneous  reaction  or  one  gradually 
becoming  more  severe,  there  is  more  likelihood  of  the  disease 
taking  a  favourable  course.  In  cases  of  cachectic  tuberculosis  the 
main  reason  for  the  absence  of  reaction  is  not  the  phthisis  but 
the  cachexia,  because  in  cases  of  slight  or  inactive  tuberculosis, 
which  are  cachectic  from  other  causes,  the  cutaneous  reaction  does 
not  usually  take  place. 

What  applies  to  the  prognostic  significance  of  the  cutaneous 
reaction  must  also  hold  for  the  conjunctival.     The  same  specific 


106  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

nature  of  the  two  reactions  is  a  proof  of  this  :  the  nature  of 
allergia  is  such  that  the  allergia  of  the  mucous  membrane  cannot 
show  more  than  the  allergia  of  the  skin.  We  have  proved  hy 
numerous  observations  [59]  that  no  prognostic  conclusions  can 
be  drawn  from  the  degree  of  the  conjunctival  reaction  and  that 
an  unfavourable  significance  by  no  means  always  attends  its 
absence  in  manifest  pulmonary  tuberculosis.  We  agree  with 
Heinemann  [114]  that  it  would  be  a  mistake  for  the  doctor  to 
give  an  unfavourable  prognosis  in  a  case  of  manifest  tuberculosis 
merely  on  the  ground  of  a  negative  conjunctival  test,  or  to  allow 
it  to  influence  the  therapy  either  as  regards  the  commencement 
of  some  definite  treatment  or  operative  measures  (abortion,  &c). 
A  method  such  as  the  conjunctival  test,  which  is  not  really 
reliable  as  regards  diagnosis,  must  be  still  less  reliable  for 
prognosis.  For  prognosis  is  only  a  more  elaborate  and  finer 
diagnosis.  At  any  rate,  we  cannot  share  the  favourable  view 
of  the  prognostic  value  of  the  conjunctival  reaction  taken  by 
Wolff-Eisner,  Meissen,  Schuster,  and  Baer. 

The  subcutaneous  test  is  of  some  assistance  in  prognosis, 
according  to  whether  it  produces  a  focal  reaction  or  not.  v. 
Romberg's  statements  [108]  may  be  quoted  in  this  respect.  On 
the  other  hand,  no  prognostic  conclusions  whatever  can  be  drawn 
from  the  size  of  the  tuberculin  dose,  the  height  of  the  fever  or 
the  curve  of  reaction. 

2.— TUBERCULIN   DIAGNOSIS  IN  TUBERCULOSIS  OF 
THE    RESPIRATORY  TRACT. 

N        .  Tuberculosis      of      the      nose      is      usually 

secondary    and    does    not    usuallv    present 

Tuberculosis.  A-  ,■      u-cc     1*.  ■  n      ■   i, 

any    diagnostic    dirnculty,    especially    when 

its  etiology  is  indicated  by  the  primary  disease.  The  solitary 
abscess  on  the  front  cartilaginous  part  of  the  septum  shows,  after 
removal  of  the  crust,  a  characteristic  appearance.  A  tuberculoma 
can  hardly  be  confused  with  a  malignant  growth.  And  in  lupus, 
which,  as  a  rule,  commences  high  in  the  front  angle  of  the 
vestibule,  nodules  spread  through  the  nostrils  to  the  outer  surface 
of  the  nose ;  in  the  later  stage  it  is  characteristic  of  lupus  in- 
filtration that  on  the  raised  tuberculated  surface,  in  addition  to 
irregular  ulceration,  there  are  necrotic  changes. 

There  are  difficulties  in  differential  diagnosis 

6  when  eczema  at  the  nostril  hides  the  process, 

also    between    tubercular    and    gummy    abscesses    and    in    those 

tubercular  and  syphilitic  processes  which  bring  about  thickening 


THE    SPECIFIC   DIAGNOSIS    OF   TUBERCULOSIS  IO7 

and  destruction  of  the  septum  and  may  even  extend  to  the  osseous 
portions  of  the  nose.  If  in  the  base  of  an  ulcer  or  in  a  piece  of 
excised  tissue  no  tubercle  bacilli  or  spirochetes  are  found,  and 
test  treatment  with  potassium  iodide  does  not  lead  to  diagnosis, 
then  tuberculin  must  be  used.  As  a  rule,  local  application  will 
suffice.  We  recommend  the  employment  of  the  nasal  reaction 
with  old  tuberculin  described  on  p.  69.  If  doubt  still  exists, 
the  subcutaneous  test  may  be  applied  with  very  careful  observa- 
tion of  any  focal  reaction.  At  any  rate,  where  tubercle  of  the 
nose  is  suspected,  diagnosis  must  under  no  circumstances  be 
abandoned  half-way.  The  practitioner  must  do  more  than 
hitherto;  only  in  this  way  will  the  deplorable  number  of  victims 
be  reduced  who  owe  their  condition  to  a  tardy  recognition  of 
nasal- lupus. 

In  tuberculosis  of  the  naso-pharyngeal  space  and  trachea, 
the  diagnostic  conditions  are  similar  to  those  in  tuberculosis  of 
the  oral  cavity,  pharynx  and  larynx;  the  following  is  a  short 
summary  :  — 

Primary  and  solitary  larvngeal  tuberculosis, 
^   °      .  that  is  cases  in  which  the  tubercular  disease 

Tuberculosis         ()f  the  )arynx  is  the  first  anc\  soje  localization 

Indications.  0f    fae    tubercular    process,    are    very    rare 

phenomena.  Laryngeal  tuberculosis  occurs,  as  a  rule,  as  a  com- 
plication of  pulmonary.  If  the  latter  has  passed  the  initial  stage 
and  is  recognizable  by  physical  and  bacteriological  examination, 
the  diagnosis  of  a  simultaneous  laryngeal  affection  will  generally 
afford  no  difficulty.  The  case  is  different  when  it  is  a  question 
of  slight  changes  in  the  lung  of  which  the  etiology  is  not  clear, 
and  where  the  laryngeal  symptoms  are  more  subjective  than 
objective.  In  such  cases  the  patient  may  complain  of  the  voice 
becoming  readily  tired,  of  some  thickness  of  speech  in  the  early 
morning  or  after  keeping  silence  for  some  time,  of  indefinite 
feeling  of  pressure  or  tendency  to  cough,  especially  on  change  of 
temperature ;  but  examination  with  the  mirror  reveals  either 
nothing  pathological  or  not  enough  to  confirm  a  suspicion  of 
specific  changes.  Acute  and  chronic  catarrh  in  tubercular 
patients,  causing  redness  and  swelling  in  the  larvnx,  may  simulate 
laryngeal  tuberculosis ;  the  same  may  be  said  of  epithelial  necrosis 
of  the  vocal  cords,  so-called  catarrhal  abscesses,  erosions  and  sore 
places  in  pachydermy  of  the  processus  vocalis  and  swelling  and 
folding  of  the  mucous  membrane  of  the  posterior  wall  of  the 
larynx. 

In  all  such  cases  the  frequency  of  tuberculosis  over  all  other 
laryngeal    affections    forces    one    to    ask    the    question    whether 


108  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

tuberculosis    is    not    present.      And    the    question    put    must    be 

answered    with    the    help    of    tuberculin    diagnosis,    as    the    same 

applies   for   laryngeal   as   for   pulmonary   tuberculosis   in    respect 

of  healing  :    the  earliest  stage  is  the  most  curable. 

.^.  .  It  is  shown  by  experience  that  the  cases  of 

Diagnosis  ,  ,   .    ,  J      ,  f 

°  laryngeal  tuberculosis  coming  up  tor  sana- 

usually  made  torium  treatment  are  in  a  large  per- 
too  late.  centage    further    advanced    than    those    of 

pulmonary  disease.  This  is  the  more  striking,  since  the  diagnosis 
of  commencing  laryngeal  disease  is  the  easier,  the  explanation 
doubtless  being  that  the  practitioner  in  general  examines  the 
larynx  too  little  and  too  late,  and  often  for  the  first  time  when 
severe  pain  on  swallowing  or  permanent  hoarseness  is  complained 
of.  It  should  hence  be  made  a  rule  to  examine  the  larynx  where 
pulmonary  disease  is  suspected  and  vice  versa,  and  to  observe 
the  result  of  the  tuberculin  injection  both  on  lung  and  on  larynx, 
since  for  the  latter  the  question  is  so  easily  and  certainly  decided. 

To  establish  the  diagnosis,  tuberculin  may  be  necessary  in 
the  presence  of  ulceration  of  the  larynx,  which  the  clinical 
history,  constitution,  and  signs  leave  doubtful  whether  of  parasitic, 
of  syphilitic  or  of  malignant  nature. 

In  the  case  of  new  growths — fibroma,  papilloma,  carcinoma — 
microscopic  examination  of  a  piece  of  excised  tissue  will  lead 
certainly  to  the  diagnosis.  But  for  the  practitioner  the  technique 
is  usually  impracticable.  If  syphilis  is  suspected,  a  therapeutic 
injection  of  salvarsan  or  large  doses  of  potassium  iodide  may 
produce  a  healing  tendency  and  disclose  the  etiology;  but  there 
are  many  cases  in  which  salvarsan  cannot  be  used,  an  anti- 
syphilitic  cure  postpones  the  diagnosis  too  long  or  does  not  give 
a  definite  result  {e.g.,  in  the  not  infrequent  mixed  forms  of 
syphilis  and  tuberculosis).  Hence  in  these  cases  it  is  well,  as 
Neisser  [115]  proposes,  never  to  leave  the  diagnostic  tuberculin 
injection  untried. 

n,     .         f  In   regard  to   the   choice  of  the   diagnostic 

Onoice  ot  111  •  1        •         •  1 

method,  the  same  considerations  in  general 

apply  as  for  pulmonary  disease.     But  the 

superiority   of    the    subcutaneous    method    deserves    still    greater 

emphasis  in  laryngeal  tuberculosis.     For  the  observation  of  the 

focal  reaction,   making  the  diagnosis  a  matter  of  certainty,   the 

conditions  are  much  more  favourable  than  in  the  lung. 

<->.  r  The    signs    of    the    focal    reaction    in    the 

.  larynx   are   also   those   of   inflammation;    in 

the    case    of    closed    foci,    of    inflammatory 


THE    SPECIFIC   DIAGNOSIS    OF   TUBERCULOSIS  IOQ 

swelling  and  redness ;  in  open  ones,  of  superficial  necrosis.  The 
reactive  processes  can  be  so  exactly  followed  with  the  mirror  that 
laryngeal  tuberculosis  may  be  excluded  when  the  picture  remains 
the  same  before,  during,  and  after  the  injection.  Generally  in 
the  course  of  the  reaction  fleeting  pains  occur  or  become  more 
noticeable,  or  at  any  rate  a  "  curious  feeling  as  if  something  were 
in  the  larynx  "  is  noted. 

The  voice  also,  where  the  focus  lies  in  the  parts  concerned 
with  its  production,  becomes  less  clear.  On  the  other  hand, 
even  in  cases  of  advanced  disease,  swelling  resulting  in  obstruc- 
tion of  the  lumen,  with  stridor  and  difficulty  of  breathing,  does 
not  occur,  a  fact  specially  emphasized  by  B.  Frankel  [116].  But 
for  these  cases,  as  has  been  said  before,  there  is  no  question  of 
employing  the  method  at  all.  Softening  of  the  process  in  connec- 
tion with  a  focal  reaction  may  occur,  but  only  in  those  tubercular 
changes  of  the  larynx  which  are  destined  to  break  down  even 
without  reactive  inflammation  and  must  soften  and  be  cast  off 
to  bring  about  a  cure.  Therefore  there  is  no  reason  why  the 
subcutaneous  test  should  be  rejected  or  postponed,  or  less 
certain  diagnostic  methods,  impracticable  for  the  practitioner, 
be  recommended.  Spreading  of  laryngeal  tuberculosis  after 
diagnostic  injections  has  never  been  observed.  The  dangers 
are  theoretical  and  warnings  against  the  use  of  tuberculin  for 
early  or  differential  diagnosis  on  the  ground  of  focal  reactions 
are  unjustified. 

3.— TUBERCULIN    DIAGNOSIS    IN    TUBERCULOSIS    OF 
THE   DIGESTIVE   ORGANS. 

In    the   oral   cavity,   tuberculosis   is   chiefly 
Mouth.  localized  in  the  tongue,  cheeks,  lips,  palate, 

mucous  membrane  of  the  gums,  and  in  the  tonsils.  In  addition 
to  the  ulcer  form,  there  occurs  the  tuberous  form  and  lupus  in- 
filtration. All  three  forms  often  present  a  certain  amount  of 
difficulty  in  differential  diagnosis,  especially  in  distinguishing 
from  cancer  and  syphilis.  If  careful  inquiries,  appearance, 
histological  and  bacteriological  examination  of  the  secretion  from 
the  ulcer  or  piece  of  excised  tissue  and  a  therapeutic  course  of 
potassium  iodide  or  salvarsan  all  fail  to  give  a  clue,  then  tuber- 
culin diagnosis  may  be  used  with  advantage.  Of  the  various 
methods,  the  subcutaneous  is  the  best,  as  it  brings  about  charac- 
teristic focal  reactions  in  tubercular  processes  in  the  mouth  which 
are    easily    recognized    in    visible    situations. 


HO  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

The    same    applies    to    tuberculosis    of    the 
Pharynx.  pharynx,  which  is  observed  in  miliary  form, 

as  diffused  infiltration  and  as  lupus.  Here  again,  owing  to  the 
great  possibility  of  mistaking  tubercular  changes  for  syphilitic, 
test  tuberculin  injections  are  often  indispensable  and  afford  the 
desired  clue. 

In    the    diagnosis    of    the    very    uncommon 
"     °  tuberculosis  of  oesophagus  and  stomach,  we 

Stomach.  have   found   that   tuberculin    is   of   no   use. 

Petruschky  and  E.  Fischer  recommend  the  subcutaneous  method 
where  tuberculosis  of  the  stomach  is  suspected,  as  it  may  produce 
indubitable  focal  reactions.  As  such  Fischer  has  observed  increase 
of  spontaneous  pain  on  pressure  and  nausea.  But  we  must  offer 
this  warning  :  In  individuals  with  completely  sound  stomachs 
and  lungs,  a  tuberculin  reaction  may  produce  sudden  gastric 
symptoms  with  nausea  and  increased  pain  on  pressure,  in  the 
tracheo-bronchial  glands  by  irritation  of  the  vagus.  This  is 
easily  explained  by  the  anatomical  situation  of  vagus  and  hilus 
glands,  by  the  frequent  tubercular  infection  of  the  latter,  and  by 
the  significance  of  the  vagus  as  a  motor,  vascular,  reflex  and 
sensory  nerve  for  the  stomach ;  and  this  is  certainly  much 
more  often  the  cause  of  a  reaction  than  a  tubercular  gastric 
ulcer. 

Owing  to  the  almost  exclusively  secondary 
n  es  mes.  character  of  intestinal  tuberculosis  in  adults, 

tuberculin  diagnosis  can  have  no  practical  value;  even  from  the 
subcutaneous  test  no  topical  diagnosis  can  be  expected.  Only 
where  a  tubercular  primary  affection  is  not  capable  of  clinical 
proof  or  its  tubercular  nature  not  settled  beyond  doubt,  can 
specific  diagnosis  explain  the  state  of  affairs  to  a  certain  degree. 
This  will  be  the  case  chiefly  in  primary  intestinal  and  mesenteric 
glandular  tuberculosis  of  childhood  and   youth. 

As  for  the  differential  diagnosis  of  ileo-cagcal  tuberculosis 
and  chronic  appendicitis  or  carcinoma,  which  is  of  great  difficulty 
and  practical  importance,  tuberculin  diagnosis  can  scarcely  be 
considered;  the  local  tests  are  not  likely  to  succeed  and  the  sub- 
cutaneous method  is  usually  contra-indicated.  The  production 
of  a  focal  reaction  is  specially  to  be  avoided  when  the  constant 
painfulness  of  circumscribed  areas  of  the  abdomen  point  to  the 
presence  of  circumscribed  peritonitis  as  a  result  of  deep  ulceration 
of  the  intestine. 

Fistulas  around  and  about  the  rectum  and  anus,  and  rectal 
ulcers,  secrete  more  freely  after  tuberculin  injections  when  they 
are  of  a  tubercular  nature. 


THE    SPECIFIC   DIAGNOSIS    OF   TUBERCULOSIS  I  I  I 

4.— TUBERCULIN     DIAGNOSIS    IN     UROGENITAL 
TUBERCULOSIS. 

Tuberculin  is  being  used  in  the  diagnosis  of  tuberculosis  of 
the  bladder  and  kidneys  and  in  urogenital  tuberculosis,  although 
urologists  and  gynaecologists  are  not  agreed  in  all  points. 

_  Of    the    local    tuberculin    tests,    an    attempt 

Cutaneous  .  -,  .  x 

was  first  made  to  use  the  cutaneous  inocu- 
lation. Thus  Hohlweg  [131],  in  the  Giessen 
Clinic,  observed  twelve  positive  reactions  to  25  per  cent,  old 
tuberculin  in  thirteen  cases  of  tuberculosis  of  the  urinary  passages, 
but  could  not  draw  any  conclusions  as  to  the  presence  of  tuber- 
culosis of  the  urinary  apparatus  itself.  Veit,  Kraus,  and  Kaminer 
have  given  emphatic  warnings  against  gynaecological  operations 
dependent  upon  the  result  of  cutaneous  inoculation.  The  in- 
terruption of  pregnancy,  too,  because  of  positive  cutaneous  re- 
action, is  not  allowable,  especially  as  R.  Stern's  [132]  systematic 
experiments  have  shown  that  the  practical  utility  of  the  cutaneous 
test  is  considerably  reduced  during  the  second  half  of  pregnancy. 

_,  .         The   conjunctival   tuberculin    test   has  been 

Conjunctival  ,        ,  • 

employed  in  urology  with  unequal  success. 

According  to  Necker  and  Paschkis  [133], 
who  use  the  tuberculin  of  the  Pasteur  Institute,  a  positive  con- 
junctival reaction  is  of  assistance  in  urology,  especially  in  dis- 
tinguishing suspicious  cases.  Casper  [134]  and  Karo  [135],  on 
the  contrary,  both  report  most  striking  errors  in  diagnosis  :  it 
was  negative  in  a  number  of  cases  in  which  operations  revealed 
tuberculosis  of  the  urinary  passages  and,  on  the  other  hand,  the 
reaction  was  positive  without  the  diagnosis  of  tuberculosis  of  the 
kidneys  being  confirmed  by  the  operation.  Hohlweg  [131],  in 
seventeen  cases  of  definite  tuberculosis  of  the  urinary  passages, 
only  found  four  distinct  and  two  feebly  positive  conjunctival  re- 
actions, eleven  being  negative.  Similarly  Horrmann  [136]  found 
the  test  of  little  use  in  one  of  the  Munich  gynaecological  clinics;  in 
no  case  did  the  conjunctival  test  definitely  decide  the  tubercular  or 
non-tubercular  nature  of  genital  complaints.  Stern  also  states 
that  pregnancy  in  itself  influences  the  diagnostic  value  of  the  test. 
Further  experiences  need  not  be  demanded  after  the  proceed- 
ings of 'the  Fourteenth  German  Congress  for  Gynaecologv  (1911)- 
The  operations  in  question  are  usually  radical  and  indications 
for  operative  measures  cannot  be  drawn  from  a  quite  uncertain 
diagnostic  method. 

Value  of  ^e  subcutaneous  tuberculin  test  gives  rise 

^   .  in  a  large  percentage  of  cases  to  focal  re- 

Subcutaneous  ■  •  •  ■  i-U-l-x  , 

actions,   increase  in  susceptibility  and  sub- 
jective    symptoms,    which    may    be    of    the 


112  TUBERCULIN    IN"    DIAGNOSIS    AND    TREATMENT 

utmost    value    in    the    diagnosis    of    tubercular    disease    of    the 

uropoietic  and  genital  apparatus. 

-,.,      r-       ,  ,-,        ..        In    vesical    tuberculosis    the    focal    reaction 
The  Focal  Reaction  .  .  .  .  .         , 

__  .         consists  of  frequent  micturition  of  an  urgent 

in  Tuberculosis        ,  .  ,     {       •      •     .,  f  +u 

character  and  of  pain  in  the  region  of  the 

of  Bladder;         biadder. 

t-   .  .     .         In  tuberculosis  of  the  kidneys,   painfulness 

in  Tuberculosis  . 

in  the  region  of  these  organs  gives  a  clue 

o  i  neys  ,  tQ  ^  gjte  Q£  ^  disease .  j-,^  our  observa- 
tions, with  those  of  Pankow,  show  that  uni-  or  bilateral  painful- 
ness in  a  focal  reaction  does  not  definitely  decide  whether  one  or 
both  kidneys  are  affected.  Besides  pain  in  the  kidneys,  other 
phenomena  come  into  consideration  as  focal  reactions  :  Difficult 
micturition,  haemorrhage,  passing  of  shreds  and  dragging  pain 
in  the  ureter  (Hock,  Karo,  Bruckner,  Hohlweg).  The  latter,  by 
limiting  his  maximum  diagnostic  dose  to  i  c.mm.  of  old  tuber- 
culin, has  observed  only  a  focal  reaction ;  this  dose  is  clearly  too 
small  even  for  the  diagnosis  of  tuberculosis  of  the  kidneys.  We 
must  agree  with  Hohlweg  that  cystoscopy  and  catheterizing  of  the 
ureters  in  combination  with  a  search  for  bacilli  is  the  most 
reliable  method  for  the  diagnosis  of  tuberculosis  of  the  kidney  ,* 
but  search  for  bacilli  in  the  majority  of  initial  cases  is  by  no 
means  the  quickest  method,  and  cystoscopy  and  catheterizing  of 
the  ureters  are  often  enough  unsuccessful  even  in  skilled  hands. 
Thus  Briicker  has  lately  published  a  case  of  a  patient,  aged  12, 
in  whom  the  consultant  physician  excluded  cystoscopy  as 
technically  impracticable  and  was  unable  to  answer  the  question 
of  which  kidney  was  diseased.  In  this  difficult  situation,  which 
occurred  in  spite  of  modern  urological  methods  applicable  to 
children,  a  topical  diagnosis  was  made  by  means  of  the  sub- 
cutaneous test  and  the  diseased  kidney  removed  by  operation. 

r.  ..      —     i.  .    In  tuberculosis  of  the  testis  and  epididymis 

of  the  Testis  and      ,  ,  „  ....  r        J       . 

there   follows   on    the   injection   a   sense   01 

pi    1   ymis,  dragging    in    the    cord,    tenderness,    pain, 

swelling,  or  even  abscess  formation  at  the  site  of  the  affection. 

c  .,       v,     •  In     vaginal    and    vulvar    tuberculosis    the 
of  the  Vagina  &  .  ....  ,     . 

,  svmptoms  of  reaction  are  visible  and  of  use 

and  Vulva  ;  ■      ,. 

'  in  diagnosis. 

r  .,  In   urogenital  tuberculosis,   also,   when   not 

.     ,  too  old  and  not  yet  begun  to  heal,  a  focal 

Urogenital  .•  ,;  ,  .  , 

&  reaction    generally     occurs,    which     varies 

Organs ;  according    to    the    site    of    the    tubercular 

affection.      Birnbaum    [137]    observed   focal   reactions   in   94  per 

cent,  of  cases  of  urogenital  tuberculosis  in  women  ;  he  therefore 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  113 

considers  the  diagnostic  tuberculin  injection  to  be  "  an  aid  at 
some  times  indispensable  and  of  primary  importance  in  the 
diagnosis,"   and   that   it   deserves  wider   recognition. 

In  tuberculosis  of  the  female  genital  organs 
the     reaction     produces     severe    abdominal 
Female  Genital      pajn>   with  bearing  down  and  a  feeling  of 
Organs.  weight  in  the  pelvis.     When  the  uterus  is 

the  seat,  pain  is  present  in  the  hypogastrium  and  sacral  region, 
sometimes  also  bleeding ;  digital  examination  will  then  generally 
make  it  easier  to  decide  whether  the  reaction  is  taking  place  in 
the  uterus  or  appendages.  Prochownick  [138]  obtained  the  best 
diagnostic  results  in  genital  tuberculosis  in  women  by  using  the 
subcutaneous  method,  so  that  he  has  remained  faithful  to  it  ever 
since  the  discovery  of  tuberculin.  Kronig,  too,  states  "  only 
subcutaneous  old  tuberculin  injections  have  a  diagnostic  signifi- 
cance "  ;  but  he  adds  that  for  clinical  use  they  have  the 
disadvantage  of  a  result  deferred  often  by  ten  to  fourteen  days 
and  of  disturbing  the  general  well-being  by  the  general  reaction. 
The  opposite  view  is  taken  by  Schlimpert  and  Zoeppritz  [139], 
who,  in  the  German  Gynaecological  Society  at  Munich,  in  191 1, 
rejected  all  the  tuberculin  tests,  including  the  subcutaneous,  as 
unreliable,  v.  Franque  [140]  also  considers  it  "  not  quite  re- 
liable "  in  gynaecology;  he  states  that  the  focal  reaction  is  often 
negative,  or  focal  and  general  reaction  takes  place  without  any 
trace  of  tuberculosis  being  subsequently  found  in  the  sexual 
organs,  especially  in  haematoma  of  the  ovary.  Neu  states  that  he 
has  repeatedly  observed  rapid  deterioration  of  the  condition  even 
after  a  cutaneous  test,  while  Birnbaum,  on  the  ground  of  his 
observations  on  gynaecological  cases  of  tuberculosis  in  the 
Gottingen  Clinic,  continues  to  affirm  that  he  has  never  observed 
spreading  of  the  disease  to  other  organs  or  an  aggravation  of  the 
tubercular  process  as  a  result  of  the  injection. 

5.— TUBERCULIN   DIAGNOSIS  IN  TUBERCULOSIS  OF 
THE  SEROUS  MEMBRANES. 

Of  tuberculosis  of  the  serous  membranes,  those  of  the 
meninges,  pleura,  and  peritoneum  must  be  mentioned  on  account 
of  their  relative  frequency. 

Contra-indication    ^    ^as    already    been    mentioned    that    on 

,         -r   .           .  suspicion     of     tubercular     meningitis,     the 

when   Tubercular  ,                                   ,     .                   .    ,. 

.  subcutaneous    method     is    contra-indicated 

Meningitis  is  because  of  the  risk  of  shortening  life.     In 

Suspected  ;  children  the  alternative  of  the  cutaneous  test 


1 14  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

is  offered,  in  adults  either  of  this  or  the  conjunctival.     It  is  true 

that  both  have  the  disadvantages  of  being  often  negative  in  cases 

of  meningitis,  and  the  failure  of  the  reaction  to  appear  does  not 

therefore  exclude  tubercular   meningitis.     Therefore    Engel    [71] 

recommends  the  intracutaneous  test  which,  he  states,  does  not  fail 

in  tubercular  meningitis  of  children.     In  adults  also  the  positive 

reaction  is  of  no  indisputable  significance. 

_  In  pleurisy  with  exudation,  the  subcutaneous 

in  Cases  of         ,   -f       ..  J  .     ,   ,       ,.  .     .       . 

tuberculin  test  tor  diagnosis  is  also  contra- 

rieunsy  ,  indicated.     Even  after  the  acute  symptoms, 

fever,  exudation,  &c,  have  passed  away,  the  question  of  practical 

moment— was  the  pleurisy  of  tubercular  origin  ? — will  not  always 

be  clearly  answered,  because  when  exudate  or  great  thickening  of 

the  pleura  is  present  the  reaction  will  hardly  be  evident,  or  if  it 

occurs  may  be  due  to  some  other  focus   having   no  connection 

whatever  with  the  pleurisy. 

On  the  other  hand,  in  cases  of  dry  pleurisy  a  conclusion  as 

to  its  tubercular  nature  may  be  drawn  from  the  general  reaction 

with  increased  pain   in   the  side  and  increased  or  more  distinct 

friction  sounds,  and  the  plan  of  treatment  adopted  in  good  time. 

Local  tuberculin  tests  may  be  specially  useful  in  diseases  of  the 

pleura    when    the    subcutaneous    method   is    contra-indicated    on 

account  of  unstable  or  raised  temperature.     Employed  with  the 

necessary  discrimination,   they  will  contribute  in  throwing  light 

on  the  etiological  side  of  the  question. 

,_.     ..  ,         The  tuberculin  injection  has  high  diagnostic 

in   Peritoneal  .  J  .         .    fc -     ,     &, 

value  in  those  cases  ot  peritoneal  tubercu- 

Tuberculosis.        1     •      •        •,  •  ■.       c.  1     •         c  j-  r 

losis,  in  which,  atter  exclusion  ot  disease  ot 

the  heart,  liver,  or  kidney,  the  diagnosis  rests  between  carcinoma 
and  tubercle.  Here,  by  the  occurrence  or  absence  of  the  tuber- 
culin reaction,  the  nature  of  the  affection  may  be  cleared  up  earlier 
than  is  possible  by  any  other  method. 

The  same  applies  when  there  is  doubt  as  to  whether  a  dry 
form  of  peritoneal  tuberculosis  is  present,  or  a  chronic,  non-tuber- 
cular form  of  peritonitis.  In  peritoneal  tuberculosis  the  focal 
reaction  is  characterized  by  abdominal  pain,  feeling  of  increased 
tension,  flatulence,  vomiting,  and  frequently  more  or  less  profuse 
diarrhoea.  In  all  these  cases,  therefore,  the  conjunctival  and 
cutaneous  methods  are  less  valuable  than  the  subcutaneous  test ; 
but  it  must  be  use'd  with  caution  when  adhesion  in  the  intestines 
is  suspected.  Its  diagnostic  reliability  is  vouched  for  by  the 
statistics  of  Heimann  [141],  according  to  which  in  the  Breslau 
Clinic,  during  the  course  of  ten  years  (1898-1908),  in  each  of 
thirty-six    cases    peritoneal    tuberculosis    was    discovered    by    the 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  II5 

tuberculin  test,  and  confirmed  by  microscopical  examination  of 
excised  portions  of  the  peritoneum.  In  these  cases  also  the  focal 
reaction  was  characterized  by  profuse  diarrhoea  and  abdominal 
pain. 

6.— TUBERCULIN   DIAGNOSIS  IN  OPHTHALMIC 
TUBERCULOSIS. 

In  ophthalmic  practice  the  position  as  regards  tuberculin 
diagnosis  has  not  been  materially  altered  by  the  introduction  of 
the  methods  of  local  reaction. 

The  cutaneous  reaction  has  been  little  used 
uutaneous    lest.      -n  ophthalmic  diagnosis;  no  more  is  to  be 
expected  from  it  in  ophthalmic  than  in  other  forms  of  adult  tuber- 
culosis, i.e.,  a  certain  importance  can  only  be  attached  to  a  negative 
result. 

The  conjunctival  reaction  has  found  exten- 
Conjunctival   Test.   sive    application     in     ophthalmic    practice, 

especially  to  decide  the  question  whether  an  affection  of  the  eye 
is  tubercular  or  not,  but  certainly  has  not  proved  a  blessing  to  the 
patient. 

Without  giving  details  from  the  extensive 
6       '  literature  on  the  subject,  we  must  take  the 

view  adopted  by  ophthalmic  surgeons  (Adam,  Brons,  Collin, 
Siegrist,  Stuelp,  Waldstein,  Stargardt,  Lohlein,  Rupprecht)  that 
conjunctival  reactions  should  never  be  resorted  to  when  ophthalmic 
tuberculosis  is  suspected.  And  this  first  because  of  the  frequent 
unpleasant  and  serious  consequences  following  instillations  in 
diseased  eyes,  and  also  because  nothing  is  gained  for  the  diagnosis 
of  ophthalmic  disease  by  a  positive  reaction  ;  it  may  be  caused  by 
a  tubercular  focus  anywhere  in  the  body.  This  also  holds  good 
when  the  instillation  is  made  in  a  healthy  eye  with  positive  results. 
Therefore  the  conjunctival  reaction  is  of  no  value  in  ophthalmic 
practice.  Thus  the  ophthalmist  will,  as  Stargardt  [117]  says, 
take  special  care  not  to  employ  a  method  which  may  aggravate  the 
condition  of  a  diseased#eye  or  harm  a  healthy  one  by  a  severe, 
protracted  reaction.  And  other  physicians,  too,  will  join  in 
refusing  to  "  employ  an  organ  of  such  dignity  as  the  eye  for  this 
diagnostic  method  "  (Sahli). 

Wolff-Eisner  [84],  it  is  true,  thinks  that  danger  to  the  eye 
may  be  avoided  by  commencing  the  instillation  with  the  weakest 
dilution  of  tuberculin  1:100,000,  and  slowly  increasing  the 
strength.  But  it  rests  with  him  to  prove  that  such  dilutions  are 
on  the  one  hand  harmless,  and  on  the  other  effective  and  reliable. 


1(6  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

^   ,  The    subcutaneous    tuberculin    test,     intro- 

Subcutaneous         ,        ,    .   4      ^,  ,        ,.,    ,     • 

duced    into    the    treatment    ot    ophthalmic 

Test  Preferable.  diseases  by  v>  Hippel  [118],  is  recom- 
mended by  Haab,  Pfliiger,  Enslin,  Stock,  Jung,  Igersheimer, 
Leber,  Davids,  Bruckner,  Reuchlin  and  others,  and  has  lately 
been  described  by  C.  Hess  [119]  as  the  "most  serviceable 
diagnostic  aid."  In  face  of  the  generally  recognized  fact  that 
tuberculosis  and  syphilis  are  the  most  important  etiological  factors 
in  chronic  inflammation  of  the  iris,  ciliary  body  and  choroid,  it  is 
indispensable  to  every  oculist.  For  in  no  affection  of  the  uveal 
tract  can  a  tubercular  etiology  be  excluded  by  clinical  means  alone, 
and  further,  in  diseases  of  the  cornea  and  sclerotic  which  do  not 
clinically  suggest  tuberculosis,  doubts  must  exist  whether  a  tuber- 
cular infection  is  present.  At  any  rate,  eye  specialists  "  without 
diagnostic  injections  can  judge  the  etiology  of  many,  very  many 
cases,  onlv  by  means  of  accessory  phenomena"  (Heine  [120]). 

_        ,         ,  Diagnostic  tuberculin  injections  in  ophthal- 

Freedom  from  .  &,.  .  J  ,    ,    , 

mic  diseases  are  not  only  necessary  but  also 

anger.  harmless.     Heine   [120]    on   the  ground  of 

many  years'  observation  of  numerous  cases  in  the  Kiel  University 

Ophthalmic  Clinic  states  :    "Of  the  many  hundreds  of  our  own 

diagnostic  injections  and  the  thousands  recorded  in  the  literature 

of  the  subject,   there  is  no  report  of  any  bad  results.       On  the 

contrary,    the   common   report   of  all   workers   in   this  branch   of 

medicine  is  that  it  has  never  done  harm."     Igersheimer  [122]  states 

that  the  local  hyperemia  even  frequently  gives  a  direct  impulse  to 

absorption,    and   thereby   to    healing    of   the    tubercular    process. 

Heine  considers  the  "  receding  reaction  "  in  an  equally  favourable 

light;  this  focal  reaction  often  occurs  in  connection  with  a  positive 

subcutaneous  test ;  the  eve  reddens,  but  afterwards  becomes  less 

coloured  than  before  the  injection. 

...  r  r-       ,       The  most  valuable  diagnostic  conclusions, 

Value  of  Focal       ,    Al      .  ,  t  .    ,    °  ,  ,       ...... 

both  01  a  general  kind  and  for  the  individual 

case,  can  be  drawn  from  the  subcutaneous 
method  with  consequent  focal  reaction.  This  has  lately  been 
specially  emphasized  by  C.  Hess,  Lohlein,  F.  Schoeler,  Augstein 
and  Igersheimer,  the  last  three  pointing  out  the  absence  of  any 
injurious  effect  in  connection  with  local  reaction  in  the  diseased 
eye.  Views  only  differ  with  regard  to  the  frequency  of  the  focal 
reaction.  Whilst  Augstein  [121]  states  that  a  more  or  less  dis- 
tinct focal  reaction  in  the  front  section  of  the  bulb  with  tubercular 
adults  is  the  general  rule,  Heine,  Stock  and  others  hold  that 
this  focal  reaction,  so  valuable  in  diagnosis,  occurring  in  the 
diseased  eve  without  general  reaction,   is  bv  no  means  common. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  II7 

Therefore  they  consider  the  absence  of  focal  reaction  in  ophthalmic 
diseases  does  not  exclude  a  tubercular  etiology. 

For  the  dosage  Davids  [123]   recommends 
Dosage.  t^e    method    of    the    Gottingen    University 

Clinic  for  Diseases  of  the  Eye,  which  gives  quite  certain  results  : 
for  the  first  injection  1  c.mm.  old  tuberculin,  for  the  second 
2  c.mm.  or  3  c.mm.,  and  for  the  third  5  c.mm.  ;  more  than  5  c.mm. 
should  not  be  given,  as  other  oculists  also  agree.  F.  Schoeler 
[124]  is  even  satisfied  with  a  maximal  dose  of  about  2*5  c.mm. 
old  tuberculin,  which  he  reaches  in  very  gradually  increasing 
doses  at  the  seventh  diagnostic  injection. 

Augstein  is  still  more  cautious  in  dosage.  In  suspected 
tuberculosis  of  the  iris  he  begins  with  an  injection  of  '01  c.mm., 
and  after  each  injection  searches  for  focal  reaction  with  the  corneal 
microscope.  In  the  Tubingen  Ophthalmic  Clinic,  too,  fractions 
of  a  cubic  millimetre  are  used  for  most  of  the  cases.  Fleischer 
increases  up  to  10  c.mm.  when  it  is  a  case  of  excluding  tubercu- 
losis with  absolute  certainty.  Heine,  also,  considers  the  old 
recommendations  of  Koch  for  dosage  in  ophthalmic  affections 
quite  unjustifiable;  only  the  experience  that  quite  small  quantities 
of  tuberculin  sufficiently  explain  the  etiology  induces  him  to  begin 
with  "i  c.mm.  in  adults,  in  children  and  weakly  patients  with 
"oi  c.mm.,  afterwards  doubling  the  dose  each  time  until  a  rise  of 
temperature  occurs,  as  small  as  possible  but  definite,  v.  Michel 
does  not  employ  the  method  for  purely  diagnostic  purposes,  but 
prefers  to  begin  with  the  smaller  doses  on  a  therapeutic  course, 
when,  of  course,  the  diagnosis  is  often  made  clear. 

But  whatever  the  dosage  may  be,  great  attention  must  be  paid 
to  the  intensity  and  duration  of  the  focal  reaction  in  the  eye. 
Therefore  it  must  be  remembered  :  (1)  That  indication  for  the 
subcutaneous  test  is  limited  to  those  ophthalmic  diseases  which 
are  clinically  doubtful  or  present  special  difficulties  in  differential 
diagnosis ;  and  (2)  that  on  account  of  the  difficulty  of  recognizing 
a  focal  reaction  in  the  eye,  the  physician  should,  in  all  such  cases, 
examine  the  often  slight  changes  of  the  local  reaction  with  the 
ophthalmoscope,  observing  their  nature  and  course. 

7.— TUBERCULIN  DIAGNOSIS  IN  AURAL  TUBERCULOSIS. 

In  spite  of  the  varying  etiology  of  acute  and  chronic  inflam- 
mation and  discharge  from  the  middle  and  internal  ear,  and  the 
mastoid  process,  tuberculin  has  not  made  much  headway  as  a 
diagnostic  agent  in  aural  practice.     . 

Certainlv  doubts  do  not  often  arise,  because  the  diagnosis  of 


Il8  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

tuberculosis  of  the  ear  can  usually  be  made  from  the  local  and 
general  condition  and  proofs  of  an  underlying  tubercular  condi- 
tion are  also  fairly  frequently  given  in  the  first  stage  by  the 
presence  of  tubercle  bacilli  in  the  secretion. 

Owing  to  the  first  observations,  the  subcu- 
Subcutaneous  Test.  taneous  tuberculin  test  is  considered  uncer- 
tain and  dangerous  in  aural  diagnosis,  although  it  is  recommended 
bv  Schwartze,  Lucae,  Bezold,  Schwabach  and  Ferreri  when  the 
diagnosis  is  doubtful.  We  also  should  consider  a  focal  reaction 
in  the  internal  ear  hazardous. 

Xo  experience  is  vet  forthcoming  of  the 
Conjunctival  Test.  ya]ue  of  the  conjunctival  reaction  in  tuber- 
culosis of  the  ear.  In  this  respect  not  much  more  is  to  be  expected 
than  what  we  can  ourselves  state,  namely  that  the  negative  result 
of  the  conjunctival  instillation  does  not  prove  with  any  certainty 
the  non-tubercular  character  of  the  aural  disease.  But  if  the 
reaction  is  positive,  then  it  is  left  to  the  observation  of  the 
physician  to  decide  whether  the  tubercular  focus  is  in  the  ear  or 
elsewhere  in  the  body. 

The  conditions  are  more  favourable  to 
Cutaneous  Test.  cutaneous  inoculation,  because  in  early 
childhood  this  gives  more  definite  results  for  the  aurist.  Thus 
Schiiler  [125],  from  observations  in  the  University  Clinic  for 
Aural  Diseases  in  Heidelberg,  comes  to  the  conclusion  that  the 
cutaneous  test  in  aural  disease,  especiallv  in  children,  is  the  more 
frequently  to  be  recommended.  The  diagnostic  value  of  the 
negative  reaction  is  greater  than  that  of  the  positive,  since  the 
latter  can  only  make  a  diagnosis  of  tuberculosis  of  the  ear  certain 
in  combination  with  clinical  reasons  for  suspicion. 

8.— TUBERCULIN    DIAGNOSIS  IN  TUBERCULOSIS  OF 

THE  SKIN. 

The  polymorphism  of  tubercular  skin  affections  explains  the 

differences  of  opinion  with  regard  to  the  pathogenesis  of  many 

of  them  ;   here  we  will   onlv  mention   the   so-called  tuberculides. 

Other  inflammatory  conditions  of  the  skin  often  cannot  be  etio- 

logically  differentiated  on  the  basis  of  clinical  svmptoms  alone. 

~    .  -r  Yr>   to  the  present  the  cutaneous  test  and 

Cutaneous  Test  :      ,  r  .  .  ^      .      ,         ...  , 

the   inunction   of   tuberculin   ointment  have 

its  Advantages  and  u  1        j        ■,  ..         •         ,  ,1  .    r   , ,     , 

6  been  employed  and  there  is  not  the  slightest 

behaviour.  reason   for  including  the  conjunctival  test. 

Moreover,  the  conjunctival  test  in  cases  of  lupus  of  the  skin  is 
generally  negative,  and  in -lupus  of  the  face,  spreading  to  the  lids 
or  conjunctiva,   directly  contra-indicated.     Of  the  intracutaneous 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  I  IQ 

method  there  is  still  no  record ;  we  imagine,  however,  that  the 
intracutaneous. test  performed  in  the  neighbourhood  of  a  suspected 
focus  would  be  of  value  owing  to  the  subsequent  focal  reaction. 

From  the  results  of  cutaneous  inoculation  in  tubercular  skin 
diseases  and  in  those  in  which  the  presence  of  tuberculosis  is 
suspected,  Bandler,  Kreibich,  Doganoff,  Moro,  Oppenheim, 
Pfaundler  and  others  agree  that  a  great  difference  of  degree  in  the 
severity  of  the  cutaneous  reaction  exists  between  cases  of 
cutaneous  and  those  of  internal  tuberculosis.  Whilst  in  patients 
with  internal  tuberculosis  and  healthy  skin  only  an  ordinary 
wheal-infiltration  occurs,  in  patients  with  lupus,  large  circum- 
scribed nodules  and  lichenoid  eruptions  make  their  appearance. 
The  difference  is  generally  readily  noted.  It  is  based  on  a  specific 
hypersusceptibility  of  the  skin  to  tuberculin,  which  also  explains 
why  specially  rapid  and  severe  cutaneous  reactions  are  to  be 
expected  in  tuberculosis  of  the  skin. 

Only  in  quite  small  lupus  foci  in  the  initial  stage  does  the 

cutaneous  reaction  in  the  healthy  tissue  often  fail.     In  such  cases 

it  is  advisable  to  perform  the  test  on  the  diseased  tissue.     If  the 

focus  is  tubercular,  a  severe  reaction  then  ensues  after  eighteen 

to  twenty-four  hours,   consisting  of  redness  and  exudation  with 

subsequent  induration  or  transition  into  necrosis  (Nagelschmidt). 

By  this  method  even   the  smallest  foci  can   be   discovered   with 

certainty. 

.     ,.  ,  In     still     more     certain    and    characteristic 

Indication  for  ,  .  ,  ... 

manner    does    the    subcutaneous    tuberculin 

Subcutaneous  Test.  .     ,        ,  i       ,    .    u        ,  t     ,  • 

test    act    on    local    tuberculosis    of    skin    or 

mucous  membrane,  especially  in  the  case  of  quite  small  and  badlv 
marked  primary  eruptions,  which  awaken  the  suspicion  of  lupus 
and  lichen  scrofulosorum.  Even  in  quite  the  earliest  cases  tuber- 
culin leads  to  such  characteristic  local  changes  that  there  can  no 
longer  be  doubt  of  the  diagnosis  of  lupus.  Even  latent  lichen 
nodules  in  the  skin  may  be  rendered  visible. 

The   focal   reaction   even   to   small   doses   is 

F c\c* r\  I    I— f o n  f "t*  i  c*i ki 

usually  severe,  and  commences  four  to  six 
hours  after  the  injection,  not  infrequently  some  hours  previous  to 
the  general  reaction  (see  Chart  12);  only  when  the  bacilli  are 
enclosed  in  cicatrized  tissue,  in  necrosis  and  quite  recent  tubercles, 
the  focal  reaction  may  be  absent. 

o  ,  r        The  most  striking  and  earliest  to  appear  of 

Symptoms  of         .  f  .  *\ 

.  the  symptoms  of  focal  reaction  are  hyper- 

Focal  Reaction.  ^mia  and  swelling.  In  the  case  of  densely 
infiltrated  lupus  the  swelling  is  marked  by  its  diffuse  and  uniform 
character,    from    which    the    lupus    nodules    stand    out,     red    or 


120  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

brownish-red.     Soft  lupoid  tissue  shows  swelling  and  protrusion 

of  the   fiat  areas,   and,    where   ulceration    is   present,    as   a   rule, 

increased  secretion.     Frequently  the  solitary  nodules  which  share 

in  the  reaction  are  surrounded  by  a  whitish  areola,  and  this  again 

by  a  broad  vivid  red  band,  an  observation  first  made  by  Koch. 

After  the  fever  has  dropped,  swelling  and  redness  die  away  and 

necrotic    processes    take    the    field  :     lupus    nodules,    prominent 

before,  sink  in;  existing  ulceration  becomes  deeper;  granulations 

become  necrotic  and  drop  off,  in  extreme  cases  first  turning  black. 

Anyone  who  has  seen  a  case  of  lupus  reacting  to  tuberculin,  sub- 

cutaneously  injected,  will  never  again  have  any  doubt  as  to  the 

specific  action  of  tuberculin  on  tubercular  tissue.        In   however 

distant  a  part  of  the  body  the  injection  may  be  made,  the  process 

is  concentrated  in  and  limited  to  the  lupus  nodule. 

„     r  .  Such    observations    justify    the    preference 

Preference  given 

being    given    to    the    subcutaneous    use    of 

to  Subcutaneous     tuberculin    in    dermatology    over    the    local 

Test.  tuberculin  test,  as  is  also  done  by  A.  Neisser 

[125].         Neisser    has    clearly    demonstrated    that   the    cutaneous 

reaction  may  certainly  prove  the  presence  of  some  tubercular  focus 

or  other  in  the  body,  but  not  the  tubercular  character  of  a  definite 

cutaneous  affection  not  clinically  characteristic;  whereas  the  local 

focal   reaction   following  a   subcutaneous   injection   of   tuberculin 

definitely  testifies  to  the  tubercular  nature  of  the  diseased  focus. 

Heuck   [126]   considers  the  special   advantage  of  tuberculin 

injections  for  the  diagnosis  of  lupus  and  tubercular  skin  diseases 

to  be  that  from  the  extent  of  the  local  zone  of  reaction  one  can 

deduce  the  real  "  microscopic  "  extent  of  the  process.     The  whole 

clearly  defined  zone  of  reaction  round  the  visible  focus  of  disease 

is  to  be  considered  as  infected  with  tubercle.     That  is  important 

both  for  the  decision  of  the  question  whether  a  definite  cure  can 

be  achieved  or  not  and  for  the  treatment,  in  order  by  operation 

to  remove  all  the  diseased  part  and  to  make  sure  that  there  shall 

be  no  relapse. 

.  .  r  Since     cosmetic     grounds    are     urgent     on 

Urgency  of  r      .       %  ,       ..  °..  , 

account     of     the    favourite    localization     of 

Diagnosis  lupus,  treatment  must  not  be  delayed  until 

in  Skin  Cases.  such  irreparable  destruction  has  occurred 
that  the  diagnosis  is  no  longer  doubtful  to  the  patient  or  his  rela- 
tives. The  practitioner  is  guilty  of  a  serious  neglect  in  regard 
to  his  patient,  if,  on  the  slightest  suspicion  of  lupus,  he  does  not 
make  sure  of  the  diagnosis  in  order  to  begin  the  line  of  treatment 
chosen.  Early  and  certain  recognition  of  lupus  is  served  by  the 
cutaneous  test  or  still  more  perfectly  by  the  diagnostic  injection 
of  tuberculin. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  121 

9.— TUBERCULIN   DIAGNOSIS  IN  TUBERCULOSIS  OF 
THE  GLANDS,  BONES,  AND  JOINTS. 

Numerous  observations  testify  to  an  in- 
Cutaneous  Test.  creased  cutaneous  reactivity  of  cases  of 
surgical  tuberculosis.  But  in  employing  the  cutaneous  test, 
Wilms'  [127]  experiences  must  be  borne  in  mind  that  it  may 
prove  negative  in  cases  of  fungoid  tuberculosis  in  whatever  situa- 
tion, and  also  in  patients  who  have  not  yet  become  cachectic.  In 
general  it  is  just  the  relatively  favourable  form  of  surgical  tuber- 
culosis, particularly  of  the  cervical  glands  and  soft  tissues,  which 
is  characterized  by  very  considerable  reactions.  According  to 
observations  in  the  Heidelberg  Clinic,  it  shows  a  form  of  reaction, 
rare  and  unusually  severe  in  pulmonary  tuberculosis,  which  is  a 
favourable  prognostic  sign  of  the  energy  exerted  by  the  organism 
against  the  infection,  and  indicates  a  healing  tendency.  Weak 
reactions  or  failure  to  react  at  all  in  surgical  tuberculosis  in  the 
initial  stage  or  in  advanced  cases  are  of  unfavourable  prognosis, 
while  decreasing  reaction  on  repetition  indicates  progression  of 
the  disease  and  an  approaching  fatal  issue,  increasing  reaction  a 
favourable  healing  tendency  (Hollensen). 

The  cutaneous  reaction  in  surgical  tuberculosis  presents  the 
same  phenomena  whether  the  tuberculin  is  of  human  or  bovine 
origin  ;  Detre's  modification  (c/.  p.  48)  has  no  special  significance. 

The    conjunctival    reaction    has    also    been 
Conjunctival  Test.  recommendeci  for  surgical  cases.  According 

to  Zoeppritz  [128]  it  is  always  positive  in  all  cases  of  closed  tuber- 
culosis of  bones,  joints,  and  glands  without  complications, 
whereas  in  closed  diseases  of  the  bones,  joints  and  glands  without 
any  other  proof  of  tuberculosis  a  negative  reaction  denotes  with 
certainty  the  absence  of  tuberculosis;  only  in  cases  of  fistula  and 
open  surgical  tuberculosis  was  the  reaction  less  reliable.  These 
observations  deserve  consideration,  but  only  after  further  confir- 
mation, for  especially  for  surgical  purposes  when  the  reaction  is 
positive,  in-order  to  avoid  faultv  diagnostic  and  prognostic  conclu- 
sions, one  must  always  remember  that  the  patient  only  needs  to 
have  quite  an  insignificant  and  clinically  unrecognizable  tuber- 
cular focus  (e.g.,  in  the  tracheo-bronchial  glands)  to  react  both 
quickly  and  severely. 

The     subcutaneous     tuberculin     test     often 
Subcutaneous  Test.  indicates   ajso   in    surgicai    tuberculosis  the 

site  of  the  disease  by  a  simultaneous  focal  reaction.  In  tubercular 
glands  inflammatory  swelling  may  generally  be  observed  after  the 
first  injection  of  tuberculin,  accompanied  by  definite  enlargement. 


122  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

Many  patients  first  have  their  attention  called  to  the  fact  that 
they  have  palpable  glands  by  the  pain  which  occurs  in  them. 
We  have  also  observed  this  after  a  positive  intracutaneous 
reaction ;  after  it  has  been  performed  on  the  forearm,  swelling 
and  painfulness  has  occurred  in  the  axilla. 

Even  the  subcutaneous  test  fails  to  differentiate  glandular 
tuberculosis  from  true  lymphatic  leucocythasmia ;  both  in  tuber- 
cular and  leukemic  glands  reaction  occurs.  Thus  Hegeler 
observed  a  huge  swelling  of  leukemic  glands  to  2  c.mm.  tuber- 
culin. The  same  holds  for  glandular  tumours  in  Hodgkin's 
disease,  which  react  just  like  tubercular;  here  it  is  evidently  a 
case  of  a  group  reaction. 

.      _   .  .      .        In  the  case  of  bone  and  joint  tuberculosis, 

In  Tuberculosis  ...  .      .  _.  , 

swelling     and     increased     tenderness     are 

unmistakable  signs  of  a  specific  reaction. 
Bones  and  Joints.  With  superficially  situated  processes,  more 
or  less  definite  reddening  generally  occurs  as  a  consequence  of 
the  inflammatory  hyperasmia.  According  to  Waldstrom  [129], 
the  early  diagnosis  of  synovial  coxitis  can  only  be  made  by  means 
of  subcutaneous  tuberculin  injections;  and,  indeed,  the  appearance 
or  non-appearance  of  synovial  symptoms  decides  the  question 
whether  a  tubercular  process  of  the  bone  is  isolated  or  already 
complicated  with  synovitis.  Tubercular  fistulas  secrete  more 
actively  after  tuberculin  injection,  and  by  casting  off  undermined 
pieces  of  skin  may  become  superficial  ulcers. 

No  further  reasons  need  be  given  for  recommending  the 
application  of  the  subcutaneous  tuberculin  diagnosis  for  the 
purpose  of  differential  diagnosis  in  such  local  symptoms,  per- 
ceptible to  sight  and  touch.  On  the  other  hand  positive  reactions 
have  often  not  been  confirmed  in  cases  of  surgical  disease  where 
tuberculosis  is  suspected,  so  that  the  negative  result  of  the 
tuberculin  test  seems  more  important.  They  also  appear  to  be 
not  entirely  free  from  danger.  Penzoldt  [105]  observed  in 
vertebral  caries  an  immediate  and  lasting  change  for  the  worse. 
Wolfsohn  [130]  reports  that  coxitis  scars  which  had  been  closed 
and  absolutely  without  reaction  for  twenty-two  years,  responded 
to  the  inoculation  of  a  small  quantitv  of  tuberculin  with  a  typical 
specific  reaction,  burst  and  produced  purulent  abscesses  with 
caseous  crumbling  contents.  Tubercular  abscesses  of  the  breast 
present  at  the  same  time  were,  however,  very  favourably  affected  by 
tuberculin,  and  were  healed.  The  burst  coxitis  scars  also  healed. 
This  case  is  much  quoted.  We  will  leave  it  undecided  whether 
it  is  an  advantage  or  a  disadvantage  that  tuberculosis  should  be 
disclosed  bv  means  of  tuberculin,  and  so  made  amenable  to  treat- 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  1 2% 

ment,  or  that  active  processes,  which  may  at  any  moment  flood 
the  whole  organism  with  tubercle  bacilli,  should  remain  con- 
cealed. But  it  does  not  seem  to  us  to  show  the  true  spirit  of 
criticism  to  condemn  the  subcutaneous  tuberculin  diagnosis 
because  of  a  single  case  which,  moreover,  took  a  favourable  course 
in  the  end.  Its  application  should  be  limited  as  far  as  possible, 
and  in  every  case  suspected  of  bone  or  joint  tuberculosis  Rontgen- 
ray  examination  should  precede  it.  But  when  this  and  clinical 
observation  do  not  explain  the  state  of  affairs,  then  tuberculin 
may  and  should  be  injected,  presuming  that  marasmus,  fever,  or 
considerable  pain  do  not  contra-indicate  it. 

10.— TUBERCULIN   DIAGNOSIS  IN  CHILDREN'S 
DISEASES. 

The  tendency  of  the   present  day  to  com- 
Necessitv  for  .  ■     ■ 

1        _         mence  the  fight  against  tuberculosis  in  the 

Early  Diagnosis.  years  of  chiidhood  is  doubtless  correct.  But 
if  success  is  to  be  obtained  in  tuberculosis  of  children,  we  must 
not  wait  until  the  foci  have  long  been  manifest  or  the  third  stage 
— pulmonary  tuberculosis  with  cavities — has  occurred.  A  laisser 
aller  of  the  tubercular  infection  in  childhood  is  still  very  preva- 
lent. Whilst  the  strong  movement  for  the  protection  of  infant 
life  has  reduced  the  mortality  from  tuberculosis  during  the  first 
two  years  of  life,  that  of  school-going  children  has  not  decreased 
materially  during  the  last  decade.  This  will  surely  be  altered 
when  in  every  tubercular  focus  in  the  child's  body  we  recognize 
a  danger.  And  occult  tubercular  glands  or  pulmonary  foci  are 
a  source  of  serious  harm  to  the  organism.  It  is  specially  in 
childhood  that  the  possibility  is  increased  of  a  quiescent  infection 
becoming  extended  by  an  injury  or  irritation  of  some  kind,  and 
this  the  more  rapidly  and  generally  the  younger  and  less  capable 
of  resistance  the  children  are.  Therefore  the  early  diagnosis  of 
infantile  tuberculosis,  including  the  occult  forms,  is  of  imperative 
necessity.     For  this  purpose  we  need  tuberculin. 

._  £        The  importance  of  the  tuberculin  test  varies 

rreciuency  ot 
,  according  to  the  age  of  the  child,  whether 

Tuberculosis    in      •,    •  ,•  (  ,  ,. 

it    is    a    question    of    sucklings,    young,    or 

Children.  older  children.     This  may  be  seen  from  the 

results  of  Hamburger's  [142]  investigations,  which  show  that  the 

frequency  of  tuberculosis  in  children  increases  proportionately  to 

advancing  age;  in  the  earliest  years  of  childhood  tuberculosis  is, 

as  a  rule,  active  and  fatal,  and  only  with  increasing  years  does 

the  frequency  of  inactive  forms  of  tuberculosis  increase.     From 


124  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

post-mortem  results,   the  increase  of  tuberculosis  from   15  to  70 
per  cent,  during  the  first  ten  years  of  life  has  been  demonstrated. 

°  With  these  observations  the  results  of  the 

Cutaneous    Test  cutaneous    tuberculin    test    are    in    striking 

with   Post-  agreement. 
mortem  Results; 

New-born  children  without  exception  give  no  reaction,  even  when  the 
mothers  react  positively.  Bondy  made  the  cutaneous  test  on  350  new-born 
children  between  the  second  and  fourth  days  of  life  and  on  their  mothers ; 
not  a  single  child  gave  a  positive  reaction,  whereas  71  per  cent,  of  the 
muthers  reacted  positively. 

Sucklings  react  but  seldom.  Tamayo  Longo  obtained  a  positive 
cutaneous  reaction  in  a  suckling  fifty-two  days  old,  whose  foster-mother 
died  of  pulmonary  tuberculosis  on  the  fifty-second  day  -post  -partinn.  In  the 
first  year  of  life  the  number  of  those  who  react  varies  according  to  the 
different  statistics  between  1  and  5  per  cent.  ;  it  is  the  highest  among  children 
taken  exclusively  from  very  bad  social  conditions,  who  had  shared  the  home 
of  parents,   foster-parents,  or  relations  suffering  from  open   tuberculosis. 

With  increasing  age,  after  the  first  year  of  life,  the  number  of  positive 
cutaneous  reactions  increases  and  generally  even  in  the  fourth  year  becomes 
so  frequent  as  to  lead  to  the  supposition  of  the  presence  of  inactive  tuber- 
culosis. The  environment  of  the  children  causes  great  fluctuations ;  while 
children  of  the  poorer  classes  react  to  the  extent  of  at  least  20  to  30  per  cent, 
of  the  total  number  to  the  first  cutaneous  test,  only  about  5  per  cent,  react 
of  the  children  of  well-to-do  parents. 

.      ...    ^..    .     .    A   similar   agreement    is   apparent    when    a 
and  with  Clinical  .         P  ,     .  ■> 

.  .  comparison  is  made  between  the  cutaneous 

reaction  and  the  clinical  condition. 

Of  clinically  tubercular  children  in  v.  Pirquet's  extensive  case-reports 
87  per  cent,  reacted,  the  remaining  non-reacting  cases  of  manifest  tuber- 
culosis being  almost  all  cachectic,  or  in  the  last  stage  of  miliary  tubercu- 
losis. Of  the  children  clinically  free  from  tuberculosis  20  per  cent,  reacted, 
rising  from  o  per  cent,  in  the  first  half  year  of  life  to  55  per  cent,  in  the 
years  from  10-14.  According  to  Feer's  investigations,  of  1,732  clinically  unsus- 
picious cases  o  per  cent,  reacted  positively  at  the  age  of  0-6  months ;  3*4  per 
cent,  at  the  age  of  6-12  months;  6  per  cent.,  1-2  years;  11  per  cent.,  2-3 
years;  17  per  cent.,  3-5  years;  22  per  cent.,  5-7  years;  29  per  cent.,  7-10  years; 
38  per  cent.,  10-15  years.  The  publications  of  Speck,  Langstein,  Aronade, 
Morgenroth,  Siegert  and  others  also  show  that  sucklings  who  are  clinically 
tubercular  and  not  yet  cachectic  or  have  only  a  few  days  to  live,  react 
positively  without  exception,  and  that  healthy  sucklings  from  surroundings 
free  from  tuberculosis  react  negatively  without  exception. 

From  such  agreement  we  may  conclude  that  there  is  a  prac- 
tically invariable  relation  between  the  cutaneous  reaction  and 
tuberculosis  in  the  organism  of  the  child. 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  1 25 

The  method  of  the  cutaneous  inoculation  in 

e  "      children   is  the  same  as   in   adults.        It  is 

forming  Cutaneous  acivisat>ie,   however,   to  consider  only  quite 

Test  on  Children,    typical    papules    as    positive,    and    atypical 

effects  of  inoculation  as  negative,  in  the  latter  case  repeating  the 

test.       Also,   should   the   first  cutaneous  inoculation   produce   no 

reaction,   it  should  be  repeated  after  one  or  more  days.       Only 

when    the    second    inoculation    produces    no    result    should    the 

cutaneous  test  be  characterized  as  definitely  negative. 

Also  in  children  it  is  not  possible  to  draw  any  conclusion 
from  the  nature  of  the  papule  as  to  whether  the  tuberculosis  is 
initial  or  obsolete,  active  or  inactive,  progressive,  or  non- 
malignant.  This  detracts  from  the  diagnostic  value  of  the 
cutaneous  reaction.  But  the  consideration  does  not  hold  in  the 
case  of  sucklings,  in  whom  there  are  no  inactive  or  healed  tuber- 
cular processes,  but  only  progressive  tuberculosis  can  be  present ; 
and  for  the  same  reason  it  need  very  rarely  be  taken  into  account 
during  the  first  year  of  life.  But  at  this  age,  too,  the  cutaneous 
reaction  is  of  greatest  significance  when  it  is  negative;  it  then 
signifies  the  absence  of  tuberculosis. 

We  can,  therefore,  summarize  thus:  — 

...  .  In     young     children     the     result     of     the 

Value  of 

cutaneous  test  is  of  greater  value  the  nearer 

es  '  they    are     to     infancy ;     in     sucklings    the 

positive  reaction  proves  the  presence  of  active  tuberculosis,   the 

negative  reaction  the  absence  of  the  disease. 

Of  older  children,  many  who  react  are  clinically  healthy, 
i.e.,  are  possessors  of  small,  inactive  foci.  In  these  cases  the 
positive  reaction  is  of  value  only  so  far  as  it  shows  the  presence 
of  a  latent  tubercular  focus  somewhere,  while  the  negative  result 
here,  too,  is  of  greater  significance;  older  children  who  do  not 
react  cutaneously  are  with  great  probability  not  actively  tuber- 
cular. In  any  case,  a  positive  cutaneous  reaction  in  children 
over  5  years  of  age  must  not  be  estimated  too  highly. 

Nevertheless,  the  special  advantages  of  simplicity  and 
absolute  lack  of  danger  make  v.  Pirquet's  cutaneous  reaction  the 
diagnostic  test  par  excellence  in  childhood.  Its  employment  is 
to  be  recommended  in  every  case  in  which  tubercular  trouble  is 
suspected  in  a  child  and  open  tuberculosis  is  present  in  its  sur- 
roundings, v.  Leube  specially  emphasizes  this  in  the  interests 
of  general  prophylaxis  against  tuberculosis.  The  further  question 
of  the  actual  site  of  the  tubercular  focus,  whether  a  glandular 
swelling,  thickening  of  a  joint,  pulmonary  focus,  &c,  is  of  a 
tubercular  origin  or  not,   is  not  answered  even   in  childhood  by 


J  26  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

the    appearance    of    a    papule.     Clinical    indications    and    other 

criteria  are  essential  to  determine  this. 

...       .  With    this    hint   we   want   to   warn    practi- 

Warninff 

&  tioners     against     faulty     diagnoses     which 

against  Faulty  appear  to  result  rather  frequently  from  too 
Interpretation.  schematic  an  interpretation  of  the  positive 
cutaneous  test.  It  must  always  be  borne  in  mind  that  although 
the  cutaneous  reaction  is  etiologically  of  great  value  in  childhood, 
in  sucklings  and  young  children  even  demonstrating  the  presence 
or  absence  of  active  tubercular  trouble,  it  does  not  determine 
with  certainty  whether  doubtful  affections  are  tubercular  or  not 
and  still  less  makes  a  topical  diagnosis  of  tuberculosis  possible. 
For  instance,  one  is  not  justified  in  diagnosing  pulmonary  tuber- 
culosis from  dulness  at  the  apex  of  a  lung  or  catarrh  in  the 
inferior  lobe  in  a  child  who  gives  a  positive  cutaneous  test;  the 
focus  giving  rise  to  the  reaction  may  be  in  some  small  gland. 
The  fact  must  also  be  remembered  that  the  cutaneous  reaction 
may  be  absent  in  spite  of  previous  tuberculosis  when  the  anti- 
bodies have  been  absorbed  by  other  means,  e.g.,  owing  to 
measles.  Engel  [71]  holds  that  this  source  of  error  is  avoided 
in  the  intracutaneous  test  which,  he  states,  gives  a  reaction  under 
all  circumstances  in  children  with  a  tubercular  infection. 

_.  If    inoculation    is    refused,    then    the    per- 

Percutaneous  t,     ,  .      .       '  r  .         f. 

cutaneous  method  in  the  form  of  inunction 

of    tuberculin    ointment,   recommended    by 

Moro,  may  take  its  place ;  but  it  is  less  accurate  than  the  cutaneous 

inoculation. 

_      .  ,  The    conjunctival    reaction    has    found    no 

Con  unctival  J  ...... 

great    vogue    in    children  s    practice,    and 

rightly    so.      And    it    is    highly    advisable 

rigidly  to  avoid  the  conjunctival  test  in  early  childhood.     At  the 

school  age,  too,  we  would  not  advise  its  employment.     However 

cautiously  we  go  to  work,  carefully  selecting  the  cases,  excluding 

with  the  greatest  care  those  who  have  had  previous  affections  of 

the  eye  and  having  discovered  no  sign  of  scrofula,   we  get  no 

small    percentage    of    cases    of    disagreeable    conjunctivitis    with 

tendency  to  the  formation  of  phlyctenular  and  other  permanent 

injuries  following  the  instillation.     It  should  never  be  allowable 

to  test  conjunctivally  whole  schools  or  classes  in  order  to  throw 

light   upon    questions   of   tuberculosis,    however   important   such 

questions  may  appear.     In   this   respect  the  cutaneous  and  the 

conjunctival  test  cannot  be  placed  on  the  same  level ;  the  former 

is    absolutely    without    danger,    the    latter,    even    with    the    very 

greatest  care,    not  without  danger.      In  addition,   the  diagnostic 


THE    SPECIFIC    DIAGNOSIS    OF    TUBERCULOSIS  1 27 

advantage  of  the  conjunctival  test  is  not  very  great.     Even  if  it 

diagnoses    more   active   cases    than    the   cutaneous    reaction,    yet 

30   per   cent,    of   the   inactive   forms   of  tuberculosis   still    give   a 

positive  conjunctival  reaction. 

_    ,  The  subcutaneous  tuberculin  test  in  child- 

Subcutaneous  ,  ,  1  •  ■•  ,       D- 

hood   combines,    according    to    Binswanger 

'est<  [IOI]>     tne    advantages    of    certainty    and 

harmlessness.      Its   application    is   only   considerably    limited   by 

the   readiness   with    which    little   children    develop    from    various 

causes   a   rise   of   temperature,    thus   making   it   very    difficult   to 

decide  whether  febrile  reaction   is  present  or  not.     This  applies 

specially  to  sucklings  and  to  out-patient  practice.     To  this  must 

be  added  the  reluctance  of  the  parents  or  relatives  of  the  children 

to  sanction  an  "  injection,"  so  that,  at  present,  the  subcutaneous 

tuberculin  test  is  limited  for  the  most  part  to  older  children  and 

private  institutions. 

One  positive  subcutaneous  tuberculin  reaction  in  a  child  does 
not  allow  of  any  far-reaching  conclusions  as  to  the  character, 
extent  and  prognosis  of  the  tubercular  process.  Engel  tried  to 
supply  this  deficiency  by  repeating  the  same  dose  after  the  re- 
action, increasing  it  later  and  even  applying  it  several  times.  He 
thinks  to  differentiate  between  favourable  and  unfavourable  tuber- 
culosis by  the  greater  or  less  susceptibility  to  tuberculin,  and 
specially  to  determine  or  exclude  progressive  processes,  pul- 
monary disease  or  latent  tuberculosis.  Latent  localized  glandular 
or  scrofulous  tuberculosis  will,  he  says,  react  only  once  or  twice 
to  an  injection  of  1  c.mm.  of  tuberculin  and  in  a  short  time  fail 
to  react  even  to  larger  doses.  And  children  who  react  several 
times  in  succession  to  tuberculin  doses  of  o' 1  c.mm.  and  less 
and  only  with  difficulty  or  never  become  tolerant  to  this  small 
dose,  may  be  strongly  suspected  of  pulmonary  tuberculosis,  even 
in  the  absence  of  any  physical  signs  proving  this  to  be  the  case. 

Engel's  observations  seem  to  be  noteworthy  in  so  far  as  they 
allow  of  the  conclusion  that  in  childhood,  when  tubercular  con- 
ditions are  not  so  complicated  as  in  adults,  we  have  in  the  sub- 
cutaneous tuberculin  test  a  means  of  distinguishing  between 
latent  and  progressive  tuberculosis.  This  would  make  the  sub- 
cutaneous tuberculin  diagnosis  also  valuable  in  the  prognosis  of 
tuberculosis  in  children.  In  any  case,  Engel's  method  must 
stand  the  test  of  time  in  the  children's  hospitals  and  sanatoria. 

In  practice  the  application  of  the  subcutaneous  method  will 
be  reserved  for  those  children  suspected  of  tuberculosis,  in  whom 
the  cutaneous  test  has  not  removed  all  doubts  as  to  diagnosis. 
If   in   such   cases   there   should   be   fever   or   some   other   contra- 


128  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

indication  of  rhe  subcutaneous  method,  then  the  needle  track 
reaction  of  Escherich  with  certain  precautions  should  be  con- 
sidered. 

For  patients  at  the  age  of  puberty,  the  cutaneous  test  be- 
comes considerably  more  uncertain  and  unserviceable  owing  to 
the  large  percentage  of  inactive  tubercular  foci.  The  conditions 
for  reaction  are  similar  to  those  in  adults ;  both  a  positive  and 
negative  result  of  the  test  have  only  a  conditional  diagnostic 
value.  Therefore  the  same  diagnostic  measures  are  necessary  in 
puberty  as  for  adults. 


III.-  The   Specific  Treatment  of 
Tuberculosis. 


A. — General  Section. 

_,      q         ,  The  search  for  a  specific  remedy  against 

tuberculosis    is    as    old    as    the    history    of 
or  a  medicine  itself.     A  host  of  drugs  has  been 

Specific  Remedy,  recommended  for  the  purpose.  So  far  as 
any  of  them  possess  value  in  symptomatic  treatment  they  will 
maintain  a  place  for  themselves  to  deal  with  particular  symptoms 
or  to  influence  the  metabolism  in  general.  But  there  exists  no 
drug  to  which  can  be  credited  a  specific  action  against  tuber- 
culosis. With  the  discovery  of  the  tubercle  bacillus  it  became 
possible  to  test  the  bactericidal  action  of  chemical  agents  directly, 
but  the  agents  in  question,  introduced  in  various  ways  into  the 
body,  are  either  too  much  diluted  to  exert  a  sufficient  action  on 
the  tubercle  bacillus  in  the  tissues — assuming  that  the  contact 
with  the  affected  tissue  lasts  long  enough — or  there  is  danger  of 
damaging  the  tissues  themselves.  The  latter  factor  comes  into 
consideration  in  the  introduction  of  drugs  direct  into  the  lung. 
R.  Koch  himself,  through  nine  years  of  continuous  labour,  tested 
a  countless  number  of  chemical  and  pharmaceutical  substances 
for  their  power  of  destroying  tubercle  bacilli  in  the  organism. 
The  result  was  negative.  Just  as  little  right  to  be  regarded  as 
specifics  have  the  intravenous  injections  of  balsam  of  Peru,  of 
cinnamic  acid  or  of  cinnamate  of  soda  proposed  by  Landerer. 
Nor  need  we  consider  here  the  organotherapy,  with  its  reputed 
specific  preparations  of  lung  tissue,  bronchial  glands  and  lymph- 
gland  juice;  nor  the  zomotherapy  of  French  authors,  who  believe 
they  have  found  a  specific  remedy  in  muscle  plasma ;  nor  the 
hasmotherapy  by  means  of  the  blood  of  supposed  refractory 
animals,  to  which  reference  will  again  be  made  under  the  heading 
of  "  Serum  Treatment."  A  chemotherapeutic  method,  started  by 
Finkler  with  chlorides  and  iodides  of  methylene  blue  and  with 
lecithin  and  copper  compounds,  is  still  in  the  stage  of  early 
9 


I30  TUBERCULIN    IN    DIAGNOSIS    A^D    TREATMENT 

experiment,  v.  Linden  seems  to  have  succeeded  in  showing  by 
animal  experiment  that  these  chemical  substances  are  able  to 
penetrate  to  the  tubercular  tissue  and  the  tubercle  bacilli.  This 
has  sufficed  to  induce  some  enthusiastic  therapists  to  use  the  pre- 
parations for  human  tuberculosis;  Meissen  in  pulmonary  tuber- 
culosis and  Strauss  in  external  tuberculosis  and  lupus  claim  to 
have  obtained  satisfactory  results.  However,  it  is  advisable  to 
consider  the  objections  put  forward  at  the  International  Congress 
on  Tuberculosis,  held  in  191 2  and  at  the  Eighty-fourth  Meeting 
of  German  Scientists  and  Doctors,  and  for  the  present  to  remain 
sceptical  and  reserve  judgment. 

Tuberculin  therapists  have  been  reproached  with  being  in 
opposition  to  the  physical-dietetic  methods,  with  underrating  the 
results  obtained  by  them  and  with  attributing  every  success  to 
tuberculin  alone  under  the  influence  of  blind  enthusiasm.  This 
is  not  correct.  Even  the  most  prominent  representatives  of  the 
specific  treatment  of  tuberculosis  have  always  acknowledged  that 
the  hygienic-dietetic  treatment,  according  to  the  principles  of 
Brehmer  and  Dettweiler,  showed  the  curability  of  tuberculosis 
and  must  remain  the  foundation  of  the  specific  treatment.  Be- 
lievers in  tuberculin  are  aware  of  the  importance  of  understanding 
the  constitution  of  the  patient,  both  in  individual  cases  of  tuber- 
culosis and  generally  in  the  campaign  against  tuberculosis ;  they 
are  aware  too  of  the  influence  of  climate,  of  the  open-air  cure,  of 
hydrotherapy  on  the  catarrh  and  inflammatory  processes  which 
accompany  pulmonary  tuberculosis,  and  they  value  these  factors ; 
they  know  the  value  of  nutrition,  they  take  metabolism  into  con- 
sideration and  improve  a  poor  condition  of  the  blood ;  they  make 
extensive  use  of  various  methods  of  stimulating  up  the  system, 
such  as  baths,  douches,  massage,  active  muscular  exercises  at  not 
too  early  a  stage,  and  gradually  increased  outrof-door  manual 
work.  But  in  so  doing  they  do  not  abstain  from  a  direct  attack 
on  the  "  nox  " — the  tubercular  virus — and  on  the  focus  of  the 
tubercular  disease. 

The  hygienic-dietetic  treatment,  is  a  purely  constitutional 
treatment ;  it  aims  solely  at  the  increase  of  the  natural  powers  of 
resistance  of  the  diseased  organism,  by  which  means  it  shall  be 
strengthened  and  healed.  That  this  may  succeed  and  that  it 
very  often  does  so  in  initial  cases,  no  longer  needs  proof;  sana- 
toria owe  their  existence  to  the  discovery  of  this  fact.  But  in 
more  severe  cases  this  method  fails  only  too  frequently,  altogether 
in  the  short  "  cure  "  usual  in  public  sanatoria.  An  improvement 
is  attained,  perhaps  even  the  disappearance  of  the  subjective 
symptoms,  generally  a  truly  astonishing  increase  in  weight  takes 


the  specific  treatment  of  tuberculosis  131 

place  and  also  a  temporary  increase  in  bodily  power ;  but,  as  a 
rule,  the  objective  condition  of  the  lung  remains  unchanged. 
The  specific  treatment,  on  the  other  hand,  by  inoculation  of 
immunizing  substances,  takes  effect  on  the  diseased  tissue  and 
produces  results  which  are  immeasurably  superior  to  those  of  the 
hygienic-dietetic  treatment  alone. 

Tuberculin  It:  is  not  witnout  cause  tnat  lately  tuberculin 

treatment,  and  with  it  all  active  immunizing 

procedure,   has   been    reckoned   one   of   the 

Natural  natural  methods  of  healing;  the  substance 

Healing  Method,     injected     into     the     organism     is     nothing 

foreign   to  the  body,    it   helps  it  to   form   the  antibodies,    which 

it    is    not   itself   able    to   produce    in  sufficient    quantity ;   by    the 

biological  production  of  the  natural  means  of  defence  the  specific 

treatment  only  imitates  and  assists  the  spontaneous  processes  of 

self-healing.     This    is    proved    by     Lowenstein    and    Pickert's 

method  of  testing  tuberculin  immunity  by  means  of  mixtures  of 

tuberculin  serum  (  [19]  and  [18]  ).     These  authors  were  able  to 

prove  that  the  serum  of  individuals  not  specifically  treated  and 

suffering  from  pulmonary  tuberculosis  taking  an  extraordinarily 

favourable    course,    possesses    the    same    tuberculin-neutralizing 

bodies  as  the  serum  of  patients  treated  with  tuberculin — a  proof 

that  tuberculin   treatment   is,    in   the   best   sense   of   the   word,    a 

natural  method  of  healing,   only  imitating  the  natural  course  of 

cure. 

t-   .  ..  The  tuberculin   method  does  not  set   itself 

Tuberculin  .  ... 

up    in    any    way    in    opposition    to    other 

methods  of  treatment.     In   the  less  severe 

Sanatorium.  cases   these   may   suffice   to   bring   about   a 

cure  without  tuberculin,  but  in  other  cases,  especially  the  severer 

ones,    tuberculin    treatment   cannot   be   dispensed   with.      In   any 

case  the  increase  of  the  general  strength  is  a  necessary  premise, 

and  that  this  is  most  rapidly  and  best  achieved  in  the  favourable 

hygienic  conditions  of  a  sanatorium,  goes  without  saying.     The 

tubercular  patient  will  only  get  the  greatest  benefit  from  specific 

treatment    by    using    to    the    full    all    hygienic-dietetic    curative 

measures  under  the  constant  supervision  of  the  physician. 

Where  the  combination  of  these  two  methods  is  not  possible, 

one  is  obliged  to  try  and  do  as  much  as  possible  with  tuberculin 

alone,  and  certainly  more  will  be  achieved  with  it  than  with  most 

other  methods  of  treatment  used  alone.     And  it  will  generally  be 

possible  in  out-patient  practice  to  obtain,  either  fully  or  partially, 

care  and  good  food  and  the  use  of  other  curative  factors — air, 

water   and    light.      In    any   case,    the    practitioner,    when    using 


1^2  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

tuberculin,  must  never  neglect  the  hygienic-dietetic  regime,  which 
will  prove  of  the  greatest  assistance  in  increasing  and  establishing 
the  success  of  the  specific  treatment.  On  the  other  hand,  tuber- 
culin should  not  be  used  when  the  personal  or  social  conditions 
are  so  unfavourable  that  harm  to  the  organism  may  result. 

1.— GENERAL  PRINCIPLES  OF  TUBERCULIN 
TREATMENT. 

The  therapeutics  of  tuberculosis,  based  on  its  etiology,  begin 
with  Koch's  tuberculin.  In  the  theoretical  section  it  has  been 
shown  how  the  difference  in  the  site  of  inoculation  of  an  experi- 
mental animal  on  the  first  and  second  infection  led  to  Koch's 
discovery  of  the  preparation.  The  guinea-pig  has,  through  the 
first  tubercular  infection,  already  attained  such  a  degree  of  im- 
munitv  that  the  second  infection  obtains  no  hold. 

Koch    found,     further,    that    sterilized    cultures    of 

rurtner    UDServa-    tubercle   bacilli   rubbed   up   in    water   and   injected, 

tions    On  even  in  considerable  quantity,  into  healthy  guinea- 

G.,'     ..   „;_.„  pigs,  not  onlv  gave  rise  to  suppuration,  but  that  in 

uirica-pisrs.  ,    '      ,  .  ,.  .  .         r   , 

°  tubercular  animals  very  small  quantities  of  the  same 

cultures  sufficed  to  kill  within  a  short  time.  Their  lives,  however,  may  be 
saved  by  the  repeated  methodical  use  of  high  dilutions,  and  obvious  improve- 
ment obtained.  When  emulsified  bacilli  were  employed  it  was  found  that  they 
were  not  absorbed  at  the  site  of  injection,  but  remained  a  considerable  time 
unaltered,  giving  rise  to  a  local  abscess.  The  curative  substance  must  then 
be  dissolved  out  by  the  body-juices  bathing  the  bacilli,  whilst  the  substance 
giving  rise  to  abscess  formation  remains  behind  apparently  in  the  bacilli, 
or  is  only  very  slowly  dissolved  out. 

The  attempt  to  extract  this  curative  agent  from  the  bacilli 
led  Koch  to  the  discovery  of  tuberculin.  His  recommendation 
of  it  in  treatment  he  founded  on  its  specific  action  on  tubercular 
guinea-pigs  and  also  on  his  observations  with  lupus  patients. 

Koch's  Discoverv  ^n  Koch's  fundamental  researches  [3]  it  was  at 
once  clear  that  man  was  immensely  more  sus- 
Ot  I  UDerculin.  ceptible  than  the  guinea-pig  to  the  action  of  the 
remedy.  Whilst  a  healthy  guinea-pig  stood  a  dose  of  2  c.c.  or  more  sub- 
cutaneous!}- without  perceptible  harm,  one  of  o'25  c.c.  suffices  to  produce 
an  intense  action  in  a  healthy  adult  man.  Estimated  in  proportion  to  body- 
weight,  T.sWth  of  the  quantity  producing  no  perceptible  action  in  the 
guinea-pig  gives  a  marked  result  in  man. 

,    ;  With    regard    to    the    specificity    of    the    action    of 

Koch  S    Original       tuberculin    on    tubercular    tissue    Koch    has    staled 

View    of  the   Action    his   view   more   exactly.      He   expressly   emphasizes 

of  Tuberculin  t^at  tu^ercuhn  does  not  kill   the  bacilli  present  in 

the  tissues,  but  that  the  tissue  alone  which  encloses 


THE   SPECIFIC   TREATMENT  OF  TUBERCULOSIS  133 

the  bacilli  is  affected  by  the  action  of  the  remedy.  In  this  occur  well-marked 
circulatory  disturbances  and  great  metabolic  changes,  resulting  in  some 
parts  in  necrosis  and  casting  off  of  a  slough,  in  others  rather  in  the  dis- 
appearance, a  kind  of  melting,  of  the  tissue.  The  remedy  can  only  influence 
living  tubercular  tissue;  on  dead  caseous,  necrotic  tissue  it  has  no  action. 

It  is  important  for  the  proper  understanding  of  his  original 
method   of   treatment    to   appreciate    Koch's    view   of    its   action. 

Since  tuberculin  causes  necrosis  of  tubercular  tissue  and  only  acts  on 
living  tissue,  the  explanation  is  easy  of  why  it  may  be  given  in  rapidly  in- 
creased doses.  One  must  suppose  that  at  first  much  living  tubercular  tissue  is 
present  and  that  a  small  dose  of  tuberculin  suffices  to  cause  a  severe 
reaction.  But  by  each  injection  a  certain  amount  of  tissue  capable  of 
reaction  disappears  and  relatively  larger  doses  are  necessary  to  attain  the 
same  grade  of  reaction  as  before.  At  the  same  time,  a  toleration  may  make 
itself  felt  within  certain  limits;  but  when  the  initial  dose  can,  in  the  course 
of  three  weeks,  be  increased  five  hundred  fold,  this  cannot  be  held  to  be 
merely  toleration,  since  there  is  no  analogy  for  so  rapid  and  extensive  an 
adaptation. 

Koch's  In  cases  of  tuberculosis  of  the  skin,   glands,  bone 

Original  Method.    and  Joints'  IO  cmm-  were  &iven  as  an  initial  dose> 

°  and  one  or  two  weeks  later,  after  the  reaction  had 

died  away,  the  dose  was  repeated  and  persevered  with  until  the  reaction 
ceased.  In  the  case  of  phthisis  the  same  dose  was  used  at  first,  but  later 
reduced  to  i  cmm.  If  fever  resulted  from  the  injection  the  same  dose  was 
repeated  daily  until  no  reaction  followed ;  then  the  dose  was  raised  to 
2  cmm.,  until  this  also  was  borne  without  reaction,  and  so  on.  But  a 
certain  number  of  more  vigorous  phthisical  patients  were  also  treated  with 
large  initial   doses  or  with   a   rapid  rise  in  the   dosage. 

.        D         .  From  Koch's  own  statements,  patients  in  the  early 

stage  of  phthisis  were  all  entirely  relieved  of 
symptoms  of  disease  in  the  space  of  four  to  six  weeks,  so  that  they  could  be 
regarded  as  cured.  From  these  observations  he  concluded  that  early  phthisis 
was  curable  with  certainty  by  means  of  tuberculin.  In  advanced  cases 
notable  improvement  was  attained;  little  or  no  result  was  achieved  in  the 
severer  forms  with  cavity  formation  or  secondary  infection.  Koch  preferred 
the  carrying  out  of  tuberculin  treatment  in  sanatoria  to  that  in  patients' 
homes,  and  set  special  value  on  the  combination  of  tuberculin  .with 
climatic,  open-air,  and  dietetic  treatment. 

Emohasis  on  Earlv   ^^e  most  essential  point  of  the  new  method,  how- 
,  ever,    was   in   its   earliest   possible   application  ;   the 

Application.  early  stage  of  phthisis  is  the  proper  object  of  treat- 

ment, which  can  then  exert  its  full  and  complete  potency.  Hence  Koch 
exhorted  practitioners,  by  all  means  at  their  disposal,  especially  with  the 
help  of  examination  of  the  sputum,  and  in  doubtful  cases  by  the  diagnostic 
injection,  to  diagnose  tuberculosis  at  the  earliest  possible  moment.  "  The 
new  method  will  only  become  a  true  blessing  to  suffering  mankind  when,  as 
far  as  possible,  all  cases  of  tuberculosis  come  to  early  treatment  and  when 
severe  neglected  cases  no  longer  occur,  the  latter  up  to  now  forming  an 
inexhaustible  source  of  ever  fresh  infection."  This  exhortation  has  not, 
even  to-day,  lost  its  fundamental  truth,  and  merits  still  to  be  taken  to  heart, 


134  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

_  r     In  this  short  summary  of  Koch's  first  pub- 

Exaggeration  of     ,.       .  iU  i      ,  , 

_&&  hcations    appear    the    now    obsolete    views 

its  Value.  which  guided  the  administration  of  tuber- 

culin in  the  first  tuberculin  era.     The  astonishing  cures  in  the 
case  of  lupus  and  other  forms  of  tubercle  led  to  an  over-estimate 
of  the  curative  power  of  the  remedy.     With  misguided  but  in- 
telligible enthusiasm,  advanced  cases  were  treated  with  too  large 
doses,  resulting  in  too  severe  reaction,   and  obvious  and  severe 
injury   resulted   from    the   faulty    method   of   application.     Koch 
had  warned  against  it  in  vain.     An  additional  factor  was  present 
in   that  the  significance  of  mixed  infection 
Harmful   Results  :    and  influenza  was  not  then  fully  recognized. 
Virchow.  It  was  principally  morbid  anatomists  who 

recorded  harmful  results,  with  Virchow  at 
their  head,  and  to  him  has  been  ascribed  the  credit  of  bringing 
the   first  tuberculin   era  to  an   end. 

_.  .  The  unfavourable  reports  of  that  time  were 

These  also  ,     ,      „  x       ,       T      „     .  ,     . 

undoubtedly   exaggerated.      In    Koch  s   m- 

aggera  6   '         stitute,    at    any    rate,    similar    experiences 

were  not  encountered.     It  must  also  not  be  forgotten  that  post- 

viortem    observations    on    patients    who    had    been    treated    with 

tuberculin  have  only  a  qualified  value.     They  were  either  cases 

in  which  the  course  of  the  disease  could  not  be  arrested  by  the 

tuberculin  treatment  and  where  the  latter  was  therefore  ineffective, 

or  at  best  of  those  who  after  an  originally  favourable  course  of 

treatment  had  a   fatal    relapse,    and   consequently   in    whom    the 

curative   effect   of   the   tuberculin    was   scarcelv,    if   at   all,    to   be 

recognized.     If  the  morbid  anatomist  is  to  judge  of  the  action  of 

tuberculin  per  se,  it  must  be  in  cases  which  have  been  so  treated 

for  a  long  time  and  have  then  died  suddenly  or  of  intercurrent 

disease. 

_,.  The  credit  of  holding  fast  to  the  established 

H  ioneers 

value  of  tuberculin  and  bringing  it  again  to 

merited  recognition  is  due  to  a  small  band 
Modern  View.  Qf  workers.  \\Te  may  mention  the  practi- 
tioners, Goetsch,  Hager,  Krause,  Thorner,  and  in  the  front  rank 
Carl  Spengler  and  Petruschky,  of  whom  the  latter  has  been  un- 
tiring in  his  advocacy  of  tuberculin  in  speech  and  writing.  What 
the  morbid  anatomists  had  seen  to  be  the  dangerous  feature  in 
the  action  of  the  tuberculin  at  its  inception  was  the  stormy  re- 
action, which  on  the  one  hand  gave  rise  to  dangerous  destruction 
of  tubercular  tissue  and  on  the  other,  by  setting  free  the  tubercle 
bacilli,  might  lead  to  extension  of  the  tubercular  process  and  a 


fHE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS         135 

transference  of  disease  germs  to   other  organs.     This   gave  the 

indication  materially  to  reduce  the  therapeutic  doses  of  tuberculin 

and,  as  far  as  possible,  to  avoid  reaction. 

_.       ....  ,...-.      ,    This    mild    method    of    administration    was 
The  Mild   Method    .  .    ,      .     .,  ..  u-      ■ 

inaugurated    at    the    same    time,     but    111- 

0  dependently,  in   1891  by  Ehrlich  and  Gutt- 

Administration.  mann  r*^  Lichtheim  [144],  Aufrecht 
[145],  .Biedert  [146],  and  by  Petruschky  [147],  who  employed  it 
for  years  in  the  out-patient  department  of  Koch's  Institute.  In 
1901  it  was  again  brought  to  the  front  by  Goetsch  [148],  whose 
recommendation  was  based  on  the  permanent  arrests  which  he 
had  obtained  with  it,  and  it  is  with  his  name  that  the  method 
has  been  generally  associated.  This  reactionless  method  of  in- 
jection characterizes  the  modern  tuberculin  treatment  and  has  the 
following  advantages  over  the  old  procedure  :  — 

(1)  It  fulfils  the  first  axiom  in  all  medical  treatment — nil 
nocere — and  at  the  same  time  cuts  the  ground  from  under  the 
opponents  of  the  method. 

(2)  It  is  in  accordance  with  the  demand  to  avoid  reaction 
by  using  the  minutest  doses  and  yet  allows  the  highest  and  most 
potent  doses  to  be  reached. 

(3)  It  extends  the  indication  for  tuberculin  treatment  by 
bringing  the  severer  forms  within   its  reach. 

(4)  It  admits  of  the  simultaneous  and  unhindered  application 
of  other  well-proved  methods  of  treatment  and  may  be  carried 
out  in   out-patient  practice  without  sacrifice  of  occupation. 

We  will  now  turn  to  a  consideration  of  tuberculin  treatment 
in  general,  regarding  tuberculin  as  a  single  entity  and  discussing 
what  is  common  to  all  its  forms  and  characteristic  of  the  treat- 
ment in  general.  The  various  preparations  will  be  treated 
separately  in  a  later  section  and  their  method  of  production, 
dosage,  and  special  features  referred  to.  This  has  the  advantage 
of  avoiding  repetition.  But  another  motive  underlies  this  arrange- 
ment. In  surveying  the  enormous  number  of  successfully  treated 
cases  in  the  literature,  the  impression  is  at  once  gained  that  the 
choice  of  a  preparation  is  a  smaller  matter  than  the  manner  of 
its  application.  And  this  is  the  method  of  careful  individualistic 
treatment  common  to  all  tuberculin  preparations. 

r^.rr  .  Of  course,  all  preparations  of  tuberculin  are 

Differences  in  ,  ,        ,  ,  ,  •  n 

not    01    equal    value;   they   are   chienv   dif- 

ferentiated  by  their  varying  toxicity,  which 

Tuberculins.  depends  on  their  relative  content  of  bacillary 


136  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

secretions  and  extracts.  This  will  be  more  fully  discussed  in 
dealing  with  the  individual   tuberculins. 

Opinion  is  not  so  clear  as  to  the  relative  curative  power  of 
the  various  tuberculins.  Koch's  principal  preparations — old 
tuberculin,  albumose-free  tuberculin,  new  tuberculin  TR  and 
new  tuberculin  bacillary  emulsion — represent,  according  to  his 
own  experience  with  animals  and  human  subjects,  progressive 
stages  of  improvement.  Koch  himself  has  not  described  differ- 
ences in  their  effect  on  the  diseased  focus ;  nor  have  they  been 
observed  by  others  in  animal  experiment.  All  other  tuberculins 
are  made  in  accordance  with  the  principles  of  Koch  and  are 
unessential  modifications.  The  supposed  improvements,  at  pre- 
sent unproved,  consist  chiefly  in  the  removal  of  the  non-specific 
parts  of  the  tubercle  bacilli  and  the  culture  medium.  These  are 
doubtless  unimportant;  Koch  himself  eliminated  them  in  his  last 
preparation — albumose-free  tuberculin . 

Old  Tuberculin       ^ut  ^rom  our  lengthy  clinical  experience  we 

can  point  out  an  essential  difference  in  the 
causes  more  a    f  r  1Z     ,,  ,.  ,    .     .  . 

errect  of  Koch  s  preparations,  which  is  this  : 

Hyperemia  than      Qld     tLlberculin     preparations    cause    more 

the  later  severe  hyperemia  of  the   tubercular  tissue 

Preparations.        than    the   bacillary   preparations,    the    mild 

new  tuberculin   TR,   the  sensibilized  bacillary  emulsion  and  the 

very  active  Koch's  bacillary  emulsion.     The  clinical  effect  of  this 

is   the   appearance   of   much   more   severe   local    reactions  at   the 

focus  of  disease.     And   from   this   fact   certain   conclusions  may 

be    drawn    as    to    the    employment    of    the    different    kinds    of 

tuberculin. 

_.,_,..  ..         It    follows   first    of   all   that   old   tuberculin 

Old  Tuberculin  ...  ,  ... 

and    albumose-iree    tuberculin,    on    account 

D  4-      -f 

of    the    importance    of    the    focal    reactions 
Diagnosis ;  produced,    are    the    tuberculins    par    excel- 

lence for  purposes  of  diagnosis.  Moreover,  whenever  more 
active  focal  reaction  is  desired,  old  tuberculin  will  be  given  the 
preference  as  a  therapeutic  agent.  This  will  be  the  case  when- 
ever the  tubercular  focus  can  be  seen  and  felt,  in  tuberculosis  of 
the  skin,  of  the  mucous  membrane,  of  superficial  glands,  of  the 
bones  and  joints,  unless  experience  has  shown,  that  another 
preparation  has  proved  more  successful,  as,  for  instance,  in 
tuberculosis  of  the  eye,  or  when  there  is  not  any  definite 
contra-indication  to  the  production  of  severe  reaction  owing  to 
the  complication  of  another  organic  disease.  We  are  thinking 
specially  of  laryngeal  tuberculosis  accompanying  severe  pul- 
monarv  tuberculosis, 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS         137 

The  use  of  old  tuberculin  preparations  will 
and  to  also  appear  advisable  in  pulmonary  tuber- 

Produce  Severe      culosis — the  most  important  localization  of 
Focal    Reactions.     tne  disease  from  the  point  of  view  of  the 

practitioner — when  it  is  desired  to  produce 
severe  reactions  in  a  focus  which  is  uncomplicated,  well  circum- 
scribed and  not  too  pronounced — perhaps  after  the  insufficient 
effect  of  the  less  severe  method  of  injections  without  reaction. 
The  old  tuberculin  preparations — apparently  albumose-free  tuber- 
culin particularly — are  also  specially  indicated  for  cases  with  toxic 
general  symptoms;  on  the  ground  of  his  observations,  Meyer 
recommends  the  sensibilized  bacillary  emulsion  on  account  of  its 
content  of  readv-made  protective  substances.  On  the  other  hand, 
the  bacillary  preparations  are  preferable  when  the  more  severe 
focal  reactions  are  to  be  avoided,  owing  to  compact  infiltrations 
with  a  tendency  to  disperse  and  extensive  processes  over  large 
tracts  of  both  lungs  in  an  advanced  stage.  Also  it  is  well,  as  a 
precautionary  measure,  not  to  use  old  tuberculin  where  there  is 
a  tendency  to  severe  and  frequent  pulmonary  haemorrhage, 
although  we  are  not  of  opinion  that  tuberculin  is  conducive  to 
haemorrhage ;  we  will  give  more  detailed  reasons  for  this  recom- 
mendation later  when  considering  contra-indications  in  pul- 
monary tuberculosis. 

The  indications  are  similar  in  the  localization  of  tuberculosis 
of  other  internal  organs  when  it  is  more  or  less  difficult  to 
diagnose  accurately,  although  an  undesired  and  severe  focal 
reaction  is  less  to  be  feared  in  the  mild  method  and  when  great 
care  is  taken.  Where  a  particular  preparation  has  proved 
specially  valuable  in  any  particular  localization,  this  will  be 
described  under  the  organ  in  question. 

Bar'llarv  Apart    from     the    special     indications    just 

_       .  .        ,  given,   we  consider  the   bacillary  emulsion 

Emulsion  best       ;.  „,  .  r    ,,  .t  ..  , 

the  most  efficient  of  all  the  preparations  and 

recommend  it  for  general  use,  especially 
General  Use.  after  previous  treatment  with  old  tuberculin 
preparations.  We  have  achieved  the  best  results  with  bacillary 
emulsion.  We  consider  it  the  most  efficacious  of  all  preparations 
of  tuberculin.  It  proved  much  the  best  in  febrile  cases  (cf.  Charts 
23  and  24),  although  it  cannot  be  denied  that  fever  is  a  difficult 
thing  to  treat,  requiring  time  above  all  things  and  the  use  of 
other  auxiliary  measures,  such  as  rest  and  water  cure.  An  in- 
dividual immunized  to  bacillary  emulsion  gives  no  reaction  even 
to  the  highest  doses  of  old  tuberculin,  whether  of  the  human  or 
bovine  type.     This  is  a  regular  occurrence  which  we  have  often 


138  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

verified.  But  an  individual  immunized  to  old  tuberculin  and 
bovine  old  tuberculin  may  still  react  to  the  same  or  even  a  smaller 
dose  of  bacillary  emulsion  (Chart  18).  This  is  important  in 
practice,  inasmuch  as  when  it  is  desired  to  continue  or  increase 
the  influence  of  tuberculin  in  patients  who  have  already  received 
the  maximum  dose  of  old  tuberculin,  they  can  be  suitably  treated 
with  bacillary  emulsion.  But  in  passing  from  old  tuberculin  to 
bacillary  emulsion,  the  dose  must  be  reduced.  We  shall  return 
to  this  point  later.  This  method  of  previous  treatment  with  old 
tuberculin  and  final  treatment  with  bacillarv  emulsion  has  proved 
of  great  service  to  us  in  many  cases  :  after  having  attained  toxic 
immunity  one  seeks  to  approach  bacterial  immunity. 

Previous  treatment  with  preparations  of  old 
Preferably  tuberculin   can,    however,    be  recommended 

Preceded  by  Old     for  the  following  reasons  :  As  the  bacillary 
Tuberculin.  emulsion   contains  all   the  active  principles 

of  the  tubercle  bacilli,  this  preparation 
makes  the  greatest  demand  on  the  diseased  organism.  It  is  more 
difficult  to  attain  immunity  to  bacillary  emulsion  than  to  any 
other  preparation  of  tuberculin.  In  advanced  cases  of  tubercu- 
losis, even  quite  small  doses  produce  very  strong  febrile  reactions 
but  no  focal  reactions — in  contradistinction  to  old  tuberculin. 
It  is  possible  that  there  may  be  to  some  extent  lytic  reactions ; 
in  human  beings  this  is  very  difficult  to  prove  by  experiment, 
but,  in  any  case,  increase  of  sputum  and  of  bacilli  is  a  very 
frequent,  if  not  a  regular  phenomenon  after  reactions.  The  con- 
ception of  bacteriolysis  is  certainlv  playing  a  larger  part  of  late 
in  the  tuberculin  reaction.  If  this  idea  of  the  procedure  of 
bacterial  immunization  by  bacillarv  emulsion  is  correct,  then 
the  fever  is  to  be  attributed  to  an  absorption  of  the  toxins 
set  free  by  the  destruction  of  the  tubercle  bacilli.  Xow  we 
know  that  we  must  distinguish  between 
The  Ideal  tox-immunity      and      bacterial      immunity, 

Immunization  :       and  tuberculosis  itself  is  the  best  example 
Simultaneous  Pro-  of    this    distinction;    tuberculin     immunitv 
duction  of  Antitoxic  does     not     mean      immunity     to     tubercle 
and   Bacterial        bacilli.     The  ideal  immunization  would  be 
Immunitv  ^e    sn:nultaneous    production    of    an    anti- 

toxic and  bacterial  immunitv. 

The  Double         ^°    ^    ^e    ^e^r^e    reaction    produced    by 
_  treatment  with  bacillarv  emulsion   mav  be 

Treatment.  •    ,  .    •,         ...  t1         '     ,  .  ,   ,_.   J 

interpreted  partially  as  a  bacteriolytic  pro- 
cess, then  the  fever  caused  by  the  dissolution  of  the  bacilli  could 
be    effectively    met    by    previous    treatment    with    old    tuberculin 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS         1 39 

preparations,  toxic  immunity  being  first  created.  However  it 
may  be  with  the  complicated  process  of  immunization  in  cases 
of  tuberculosis,  we  have  attained  the  best  results  by  taking  the 
treatment  with  old  tuberculin  preparations  up  to  the  maximal 
dose  or  to  a  relatively  high  toxic  immunity  (up  to  ioo  or 
200  c.mm.)  and  then  continuing  with  bacillary  emulsion. 

The  dosage  of  the  bacillary  emulsion  can  be  increased  much  more 
rapidly,  as  it  is  tolerated  infinitely  better.  It  is  not,  however,  absolutely 
necessary  to  go  back  to  the  initial  dose  usually  given,  about  the  hundredth 
part  of  the  previous  dose  of  old  tuberculin  being  suitable.  For  instance,  if 
one  has  given  10  divisions  of  dilution  I  of  old  tuberculin,  then  1  division  of 
dilution  II  of  the  bacillary  emulsion  may  be  used.  If  the  maximum  dose — 
10  divisions  of  old  tuberculin — has  been  reached,  then  as  a  rule  1  division 
of  dilution  I  of  bacillary  emulsion  will  be  supported  without  reaction. 

If,  for  some  reason  or  other,  a  change  is  made  in  the  preparation  used 
when  weaker  solutions  are  being  injected,  then  one  need  only  go  back  to  the 
tenth  part  of  the  previous  dose,  for  example,  from  1  c.c.  of  dilution  III  of 
old  tuberculin  to  o'i   c.c.   of  dilution   III  of  bacillary  emulsion. 

We  have  published  details  of  our  results  in  statistical  papers  [149-]. 

It  is  a  matter  of  great  satisfaction  to  us  that  the  last  researches 
of  R.  Koch  on  the  therapeutic  use  of  tuberculin  in  human  beings 
led  him,  after  all  sorts  of  variations,  to  the  same  method  as  that 
recommended  by  Jochmann  [150]  at  the  Congress  on  Internal 
Medicine,  held  last  year.  The  results  agree  in  every  detail  with 
the  system  of  treatment  evolved  by  us  after  years  of  experimental, 
biological  and  clinical  study.  This  has  been  proved  to  us  to 
be  the  best  and  we  have  described  it  here  in  broad  outline. 

2.— METHOD  AND  GENERAL  TECHNIQUE  OF 
MODERN  TUBERCULIN  TREATMENT. 

^,     .  .  -,.,  The    usual    and    most    suitable    method    of 

Choice  of  Site  ....  «         :.    -  ,         ,  . 

administering     tuberculin     for     therapeutic 

or  injection.  purposes  is  the  subcutaneous.  Koch  has 
from  the  first  recommended  as  the  best  site  for  injection  the  skin 
of  the  back  between  or  below  the  shoulder-blades,  alternately  on 
each  side;  the  skin  can  here  be  raised  in  large  folds  and  there  is 
less  chance  of  a  local  reaction;  usually,  in  fact,  none  at  all.  For 
the  patient's  convenience  the  forearm  is  often  chosen,  but  the 
skin  here  is  less  readily  raised  in  folds  and  there  is  more  likeli- 
hood of  painful  infiltration.  There  is  also  the  network  of  veins 
to  be  considered,  since  damage  to  the  smaller  venules  may  occur, 
and  the  tuberculin  being  more  rapidly  absorbed,  as  in  an  intra- 
venous injection,  gives  rise  to  unexpectedly  severe  reactions.  To 
protect  against  such  unwelcome  surprises  it  is  a  good  plan   to 


I4O  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

insert  the  needle  deeply  and  withdraw  it  somewhat  before  in- 
jecting. If  many  patients  have  to  be  inoculated,  when  undress- 
ing would  take  too  long,  we  recommend  the  injections  being 
made  in  the  breast  near  the  mammary  glands,  which  only 
necessitates  the  opening  of  the  clothes  in  front.  We  have  con- 
vinced ourselves  in  the  last  few  years  by  the  treatment  of  several 
hundreds  of  patients  that  the  injections  can  be  well  tolerated 
there  and  for  the  most  part  even  completely  without  reaction. 
To  avoid  reaction  the  injections  must  be  made  into  the  loose  sub- 
cutaneous tissue  between  cutis  and  fascia  ;  those  into  the  cutis 
are  painful  and  may  at  once  be  recognized  by  the  palpable  bleb 
they  produce ;  they  are  more  likely  to  give  rise  to  infiltration, 
with  swelling,  redness,  and  occasionally  pain  of  a  dragging 
character,  which  may  extend  up  to  the  arm.  Infiltrations  vary 
very  much ;  the  more  immunizing  substances  the  preparation 
contains  and  the  more  concentrated  it  is,  the  more  pronounced 
do  thev  appear ;  earlier  after  injections  of  old  tuberculin  than 
after  a  non-concentrated  preparation,  with  more  intensity  after 
BE  than  after  TR.  They  depend  mainly  on  the  quantity  of 
the  less  soluble  substances  in  the  tuberculin.  Other  conclusions 
cannot  be  drawn  ;  thev  rest  on  unproved  hypotheses. 

~     ,  r>  1     .        It  should  be  mentioned  that  Carl  Spengler 

Carl  Spengler  s  , '       '  ^  r  r 

intentionally  chooses  the  extensor  surface  of 
Site 

the  forearm,  with  the  object  of  obtaining  a 

criterion  for  the  repetition  of  the  injections  based  on  the  greater 
sensitiveness  of  the  skin.  According  to  his  numerous  observa- 
tions there  exists  an  infallible  relation  between  the  local  reaction 
in  the  diseased  focus,  a  reaction  often  difficult  to  demonstrate  in 
pulmonary  tuberculosis,  and  the  needle-track  reaction  ;  and  this 
relation  is  to  be  interpreted  as  a  parallel  occurrence  of  chemotactic 
hyper-leucocytosis.  The  inflammatory  reaction  at  the  site  of 
injection  accordingly  gives  a  clue  to  the  intensity  and  duration 
of  the  focal  reaction,  and  the  latter  demands  a  suspension  of  the 
injections  until  all  the  symptoms  of  reaction  have  disappeared. 
Sahli  also  emphasizes  the  importance  of  the  cutaneous  reaction 
at  the  site  of  inoculation,  which  appears  to  him  most  important 
in  judging  the  condition  of  immunity. 

The    principle    of    allowing    oneself    to    be 

Cutaneous  Reaction  guided   in   estimating   the   action    of  thera- 

not   Parallel  with     peutic  tuberculin  treatment  by  the  result  of 

Focal   Reaction        the    cutaneous    reaction    (v.    Pirquet's    and 

in   Lung.  needle-track  reaction)  would  be  justified  if 

the  strength  of  the  reaction  really  were  a 
measure  of  the  reactive  inflammation  in  the  lungs.     But  such  a 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS         141 

connection  has  not  been  confirmed  either  by  us  or  by  others.  On 
the  contrary,  we  have  reason  to  think  that  cutaneous  reaction 
and  focal  reaction  are  two  phenomena  quite  independent  of  one 
another  and  are  ever  more  inclined  to  believe  that  the  degree  of 
cutaneous  reaction  depends  upon  the  general  nervous  sensibility 
to  reaction  of  the  individual.  The  more  we  have  studied  the 
conditions  of  cutaneous  reaction  during  the  last  few  years  the 
less  are  we  able  to  accept  the  proofs  which  Saathoff  [97]  tries 
to  bring  forward  in  support  of  this  theory.  There  is  no  definke- 
ness  about  it,  no  uniformity  of  interpretation  ;  we  learn  this  from 
the  comparative  observation  of  patients  suffering  from  initial  and 
from  advanced  tuberculosis,  with  acute  and  chronic  processes, 
with  favourable  and  unfavourable  prognosis,  with  well-nourished 
skin  and  the  reverse.  Among  our  numerous  tuberculin  patients 
we  have  always  some  cases  in  whom  almost  every  injection 
produces  acute  infiltration  of  the  skin  without  any  specially 
characteristic  condition  of  the  lung  or  the  temperature  curve. 
The  best  way  to  clear  up  this  question  is  to  observe  such  foci  as 
are  visible  to  the  eye.  For  example,  the  occurrence  of  a  needle- 
track  reaction  whilst  a  lupus  focus  remains  completely  without 
reaction  or  the  reverse  state  of  things  is  hostile  to  Saathoff's 
opinion.  Moreover,  we  are  acquainted  with  a  whole  series  of 
cases  in  which  individuals  clinically  perfectly  healthy  have  given 
so  severe  a  cutaneous  reaction  that  Saathoff -would  place  them  in 
his  Group  I,  who  gave  not  the  slightest  general  reaction  to 
10  c.mm.  of  old  tuberculin.     This  proves  :  — 

(1)  That  the  parallel  between  cutaneous  and  focal  reaction 
cannot  be  maintained. 

(2)  That  it  must  appear  impracticable  to  make  the  method  of 
tuberculin  treatment  and  still  more  a  subtle  dosage  of  tuberculin 
depend  on  the  amount  of  cutaneous  reaction.  The  practical  draw- 
back of  clinging  to  the  above  unproved  hypothesis  lies  for  the 
patient  in  the  continuous  use  of  too  small  doses  of  tuberculin, 
which  are  of  little  effect  and  may  lead  to  hypersusceptibility ;  we 
have  the  same  state  of  things  'here  as  in  the  abandoned  method  of 
continual  observation  of  the  opsonic  index. 

Other  efforts  to  employ  quantitative  cutaneous  tuberculin 
tests  for  the  choice  and  dosage  of  tuberculin  in  treatment 
(Autokratoff,  White,  van  Norman,  Ziiblin)  have  also  proved 
without  result  and  promise  no  better  success  for  the  reasons 
given  above. 

-  .  It   is  advisable  to  cleanse  the  spot  chosen 

with  ether  before  the  injection,  and  by  this. 

means  a  slight  anaesthetic  effect  is  also  produced.     The  cleansing 


142  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

is  not  absolutely  necessary,  as  in  a  series  of  many  thousands  of 

sanatorium    patients    where    no    disinfection    of    the    skin    was 

carried   out   there   was   no   single   case   of   suppuration    or    local 

inflammation.        In    out-patient   and   club   practice   the   puncture 

should,  however,  be  covered  up  after  the  injection  has  been  made. 

The  choice  of  syringe  has  already  been  discussed  (vide  p.  71). 

,-su.  r  The  barrel  should  be  as  long  as  possible, 

Choice  of  .        .  .  ,  °  ,       T 

_     .  so  that  the  graduation  is  widely  spaced.     It 

1      s  '  will  then  be  possible  to  read  off  twentieths 

with  accuracy,  and  so  guarantee  an  exact  dosage. 

Of  late  years  various  reasons  have  led  to  an  attempt 

Other    Methods    Of  to    administer    tuberculin    in    treatment    otherwise 

Administration.        than    subcutaneously.        These   methods  have  been 

intravenous,     intrapulmonary,     by     inhalation,     by 
mouth,  by  rectum,  percutaneous,  and  cutaneous. 

Intravpnnu^  ^  'ie  intravenous  injections  of  tuberculin  were  first 

made  and  recommended  by  Koch  [39].     He  found 
Method.  iri    his    first;    researches    into    the    agglutination    of 

tubercle  bacilli  that  the  agglutinating  power  possessed  by  the  subjects  of 
tuberculin  treatment  was  to  be  interpreted  as  an  immunizing  process,  and 
that  in  general  a  high  agglutination  value  denoted  a  high  grade  of 
immunity.  But  it  was  a  fact  of  regular  occurrence  that  the  agglutinating 
power  of  patients  treated  with  tuberculin  subcutaneously  could  be  raised 
yet  further  by  giving  the  same  preparation  intravenously,  and  this  led  to 
Koch's  recommendation  of  the  procedure.  We  [40]  have  shown  that  an 
immunity  associated  with  extraordinarily  high  agglutination  values  is  attain- 
able by  the  mild  subcutaneous  method  without  the  production  of  reaction,  so 
that  the  chief  ground  for  recommending  the  intravenous  application  is  gone. 
In  general,  between  the  action  of  tuberculin  intravenously  and  sub- 
cutaneously there  is  only  a  difference  of  degree  and  of  time ;  with  the 
former  the  reaction  occurs  very  much  sooner  and  it  is  more  severe.  But 
since  the  best  results  are  to  be  obtained  by  the  mild  method  and  this,  as  has 
been  shown,  is  eminently  the  method  of  administration,  the  intravenous 
application  need  no  longer  be  considered. 

Intranulmonarv       The   intraPulmonary  method   of  application   is  the 

so-called    lung-infusion   of   Jacob    [151].     His    aim 
Method.  was    t0   bring    medicaments    with    strongly   bacteri- 

cidal action  on  tubercle  bacilli  into  the  closest  possible  contact  with  the 
diseased  area.  This  aim  could  be  best  attained  by  introducing  a  catheter 
into  the  commencement  of  a  bronchus,  after  anaesthetizing  the  larynx  and 
trachea,  and  applying  a  definite  dose  of  the  drug  through  it.  The  most 
favourable  results  were  obtained  with  tuberculin.  The  desired  contact  of 
the  diseased  tissue  with  the  tuberculin  takes  place  under  the  most  favourable 
conditions  only  to  a.  small  extent,  and  in  any  case  is  too  brief  for  a  direct 
action,  since  the  drug  is  rapidly  removed  by  the  lymphatics.  The  method  is 
Criticism   of  based    on    an    incorrect    conception    of    tuberculin 

action.    We  are  rather  in  agreement  with  the  pointed 

I  neory.  remarks  of    Levin    [152]    in    this    connection.      He 

says  :     "  The  more   or  less   crude   attempts   to  improve  on   the   inefficiency 

of    our    therapeutic    endeavours    by   bringing  the   drug    into    direct    contact 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS  1 43 

with  the  organ  to  be  treated — e.g.,  injections  into  the  brain  or  spinal 
column,  or  into  the  air  passages — do  not  take  into  consideration  that 
a  direct  and  material  surface  action  is  but  little  attained,  since  there 
are  everywhere  present  lymphatics  and  blood-vessels,  which  quickly 
carry  away  the  drug  introduced.  Even  when  at  first  a  more  intense 
action  can  be  recognized,  this  is  soon  equalized  down  to  the  ordinary  level. 
Instead  of  better  action  there  often  appears  a  worse  one,  on  account  of  the 
damage  to  cell-life  in  such  hollow  organs  due  to  the  injection." 

-p    .  •■  Kapralik  and  H.  v.  Schroetter  [153]  drew  attention 

to    the    employment    of    tuberculin    inhalation    for 
Inhalation.  producing  immunity,  after  their  researches  had  led 

them  to  believe  that  favourable  results  were  to  be  obtained  by  this  method. 
The  proceeding  is,  in  contrast  to  Jacob's,  one  free  from  danger,  but  there 
are  no  resulting  advantages  to  recommend  it.  The  principal  disadvantages, 
on  the  -other  hand,  are  :  Uncertain  dosage  of  tuberculin ;  the  using  of 
enormous  quantities  of  the  drug  while  only  the  smallest  quantities 
are  effectively  utilized ;  the  necessary  limitation  to  small  doses,  since 
on  financial  grounds  the  amount  of  tuberculin  volatilized  cannot  be  in- 
definitely increased.  The  possibility  of  applying  tuberculin  inhalation  for 
purposes  of  diagnosis  in  accordance  with  these  authors'  methods  we  have 
been  able  to  confirm  but  only  with  different  and  varying  concentration 
[154  and  155];  the  method  appears  to  be  too  much  bound  up  with  unavoid- 
able error  to  be  trustworthy. 

q      I  The  administration  of  tuberculin  by  mouth,   which 

was  first  recommended  by  Freymuth,  father  and 
Administration.  son?  -m  the  f[rst  instance  for  diagnostic  purposes  in 
the  form  of  keratinized  pills,  is  also,  according  to  our  own  [155]  and  other 
recent  investigations  worthless  (Huhs,  Lowenstein,  Kohler,  Jochmann,  Hell, 
Mollers,  and  Heinemann) ;  for  absorption  from  the  alimentary  canal  is 
relatively  inert,  as  is  the  case  with  snake  poison  and  the  toxins  of  tetanus 
and  diphtheria.  Thus  tuberculin  both  per  orem  and  per  rectum  produces 
no  reaction  in  a  tubercular  guinea-pig  (Laffert,  Dieterlen).  According  to 
Ransom,  physical  factors  are  chiefly  responsible  for  this  result ;  all  these 
albuminoid  poisons  pass  the  epithelial  lining  of  the  intestinal  tract  only 
with  great  difficulty,  and  are  for  the  most  part  rejected  ;  but  if  the  protecting 
epithelium  is  injured  or  altered  in  any  way,  then  absorption  takes  place. 
Besides  this,  the  toxins  are  decomposed  or  attenuated  by  the  processes  of 
digestion,  and  the  mechanics  and  chemistry  of  the  stomach  vary  in  different 
individuals.  The  result  of  this  knowledge  was  the  administration  of  the 
tuberculin  in  capsules  insoluble  in  the  gastric  juice.  So  a  series  of  new 
preparations  arose,  which,  however,  soon  fell  into  well-deserved  oblivion 
on  account  of  their  ineffectiveness  and  partly  owing  to  their  excretion  unused 
a    .  •  r  p         •        through  the  intestines.     Pfeiffer  and  Trunk  were  the 

"  first  to  prove  experimentally  that  pepsin  and  trypsin 

and   Trypsin.  exert     a     more     or     less     extensive    weakening     or 

destructive  action  on  tuberculin.  At  the  instigation  of  R.  Koch,  B.  Mollers 
and  Heinemann  [156]  then  undertook  a  detailed  investigation,  and  by  means 
of  the  tuberculin  reaction,  experiments  on  guinea-pigs  and  complement 
deviation,  found  that  the  specific  active  substance  in  tuberculin  is  so  con- 
siderably damaged  by  pepsin  and  trypsin  that  the  internal  administration  of 
tuberculin  must  be  rejected  owing  to  weakening  of  the  tuberculin,  incom- 
plete absorption,  and  uncertainty  of  dose.  Especially  convincing  are  the 
recent     tuberculin     tests     on  tubercular    guinea-pigs;    those    animals    which 


144  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

received  intraperitoneal  injections  of  tuberculin  mixed  with  the  digestive 
juices  displayed  no  reaction  and  continued  to  live,  while  the  control  animals 
died  with  the  typical  phenomenon  of  "  tuberculin  death." 

According  to  Calmette's  investigations,  it  was  sup- 

Phtysoremid.  posed  that  effective  action  would  be  most  likely 
with  the  internal  administration  of  bacillary 
emulsion  in  the  form  of  keratin-coated  gelatine  capsules;  these  Krause  [157] 
gave,  with  exact  instructions  for  use,  to  patients  in  whom  regular  injections 
were  impracticable.  The  preparation  is  for  sale  under  the  name  of  Phtysore- 
mid.  But  here,  again,  B.  Mollers  and  Heinemann's  experiments  are  unfavour- 
able to  the  remedy;  even  with  doses  corresponding  to  20  c.c.  of  the  Hoechst 
bacillary  emulsion,  they  could  not  produce  a  rise  of  temperature  or  other 
sign  of  reaction  in  their  patients.  Krause  states  that  he  has  achieved  visibly 
good  results  in  glandular  tuberculosis  and  has  observed  the  healing  of  per- 
sistent fistulae.  Hager,  too,  mentions  its  efficacy  in  cases  of  surgical  tuber- 
culosis. Kohler  obtained  satisfactory  results  in  less  severe  cases ;  in  more 
severe  conditions  it  failed,  although  thirty  out  of  forty-two  patients  made 
an  extraordinary  and  unexpected  increase  in  weight,  such  as  he  had  rarely 
observed  in  forms  of  the  disease  so  unfavourably  situated. 

We  purposely  refrain  from  mentioning  other  and  similar  preparations 
for  internal  use  which  commercial  speculation  has  brought  into  the  market. 
There  is  not  the  slightest  proof  that  their  composition  is  superior,  and  there 
is  no  confirmation  by  unprejudiced,  competent  authorities  of  the  good  results 
always  claimed  for  them.  We  specially  call  to  mind  the  internal  adminis- 
tration of  tuberculin  with  guaiacum,  creosote,  iodine,  arsenic,  and  quinine, 
which  are  sold  under  the  scientific  title  of  "  chemotherapeutic  treatment  of 
tuberculosis."  Such  doubtful'  and  uncertain  remedies  are  certainly  not 
needed  for  a  rational  combination  of  tuberculin  and  arsenic  treatment. 

Administration        ^^e  recta^  administration  of  tuberculin  in  the  form 
of    suppositories    and    enemata    need   only  be   men- 

per    Kectum.  tioned  here.      There  exists  no  indication  for  it;  also 

experiments  have  shown  that,  just  as  in  the  oral  method,  the  tuberculin  is 
but  slightly  absorbed  and  in  varying,  uncontrollable  amounts.  It  is  a 
different  matter  when  it  is  a  question  of  the  absorption  of  large  quantities 
of  serum,  though  nothing  definite  is  known  of  the  laws  which  govern 
absorption  by  the  rectum  and  colon. 

Percutaneous         ^n   aPP1icati°n    ter    cutem  has    been    employed   by 
,  Carl    Spengler    in    therapy    in    the    case    of    very 

Application.  weakly   phthisical  patients    with   fever   and   hyper- 

susceptibility  to  tuberculin;  mostly,  in  fact,  children.  The  method  has 
been,  till  now,  but  little  taken  up ;  Lips  employs  it  in  the  same  way  as 
Spengler;  Krause  has  seen  no  results  from  it.  The  view  of  the  current 
text-books  of  physiology  is  that,  in  consequence  of  the  fatty  content  of  the 
normal  epidermis  and  of  the  sweat  glands,  the  skin  is  unable  to  absorb 
solid  substances  out  of  watery  solution.  Combined  with  fluids  which  dis- 
solve and  extract  the  sebaceous  matter  of  the  skin,  certain  drugs  may  be 
absorbed  in  very  small  quantity.  This  occurs,  then,  through  the  sweat 
glands  or  the  interstices  of  the  epidermal  cells.  When  energetic  rubbing  is 
carried  out  there  is  a  pressing  of  material  into  the  pores  and  a  mechanical 
loss  of  continuity  between  the  epidermis  cells  as  well  as  actual  forcing  into 
hair  sacs  and  glandular  ducts  (e.g.,  with  mercurial  inunction),  in  the  same 
way  as  an  inflamed  skin  with  damaged  .epidermis  absorbs  more  readily,  the 
conditions  more  nearly  resembling  an  ulcerated  surface;  energetic  inunction 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS  1 45 

may  lead  to  this  result,  and  the  efficacy  of  application  -per  cittern  can  be  thus 
explained.  In  any  case  the  present  teaching  of  physiologists  with  regard  to 
the  imperfect  absorptive  power  of  the  skin  needs  revision. 

Mlinch's  Munch    [158]    and    after    him    Poeppelmann    [159] 

have   used  v.    Pirquet's   cutaneous   inoculation   with 

IVletnOa.  pure   tuberculin    repeated    about    every   four   to  ten 

days  for  treatment.  Wallerstein  carries  out  an  immunizing  tuberculin  treat- 
ment on  the  same  principles,  but  using  solutions  as  weak  as  possible. 
Sahli,  too,  has  lately  tried  this  method  with  a  modification ;  he  applies 
tuberculin  in  rapidly  increasing  concentration  to  scarifications  on  the  skin 
of  as  equal  a  size  as  possible.  As  far  as  we  know,  no  clear  proofs  of  the 
value  of  these  methods  have  been  adduced. 

The  subcutaneous  method  seems  to  us  to  be  the  one  which  offers  the 
great  advantages  of  sparing  the  stomach,  absorption  in  absolutely  unaltered 
condition  and   the  most   exact   dosage. 

Observation  and     With  regard  to  the  detailed  mode  of  appli- 
.  cation,    reference    should   be    made    to    the 

°       Special    Part,    where    this    is    discussed    in 
Necessary.  detail  in  view  of  the  intention  of  the  book 

to  serve  as  a  practical  guide  to  the  practitioner ;  there  will  be  found 
the  initial  dose,  the  increase  of  dosage,  interval  between  injec- 
tions, maximal  dose,  method  of  preparation  and  keeping.  It 
need  only  be  remarked  here  that  the  principle  of  application  is  a 
slow  increase  of  dosage  under  the  most  careful  observation  and 
the  avoidance  to  the  utmost  of  severe  reaction.  No  hard  and  fast 
scheme  for  dosage  can  be  given,  but  each  individual  case  must  be 
considered  for  itself.  Cases  in  which  the  disease  is  apparently 
of  the  same  extent  may  behave  in  a  radically  different  way  towards 
tuberculin.  Thus  the  treatment  of  a  case  in  Stadium  III  with 
tuberculin  may  be  an  easier  and  more  successful  matter  than 
one  in  Stadium  I. 

Two  Contrasting     As       re«ards       dosa^e       tw0       contrasting 
. .  J_.      .  methods   have   existed  from   the  first  :     the 

Methods  c  „         ,     r  .  .  . 

use  of   small  and  of  large  doses  of  tuber- 
of  Dosage.  cuiin>       The    first    tuberculin    era    was    the 

period  of  large  doses  and  severe  reactions  which  at  that  time  were 
identical.  The  endeavour  to  avoid  dangerous  reactions  led  of 
itself  to  a  gradual  reduction  of  the  doses.  To-day  a  whole  series 
of  authors  claim  to  have  been  the  first  to  recommend  the  avoidance 
of  severe  reactions.  We  have  already  pointed  out  the  merit  of 
Goetsch.  From  that  time  dates  the  beginning  of  the  second 
tuberculin  era. 

Since  then  the  principle  has  obtained  of  avoiding  reactions 

as  far  as  possible  or  only  allowing  slight  reactions.     There  seems 

no  sufficiently  strong  distinction  drawn  between  the  method  which 

uses  only  small  and  the  smallest  quantities  of  tuberculin  and  by 

10 


146  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

so  doing  naturally  also  avoids  reactions,  and  the  mild,  cautious 
method  of  gradually  increasing  the  dose,  aiming  at  the  assimila- 
tion of  large  doses  of  tuberculin  whilst  avoiding  reaction  as  far 
as  possible  and  beginning  with  small  doses.  Moreover,  it  does 
not  appear  to  be  sufficiently  known  or  emphasized  that  to-day  the 
idea  of  larger  doses  of  tuberculin  has  no  longer  anything  whatever 
in  common  with  the  idea  of  severer  reactions.  Even  Goetsch  did 
not  remain  content  with  using  small  doses  of  tuberculin,  but 
strove  to  attain  a  high  degree  of  tuberculin  immunity.  This 
method  is  ours  also,  and  is  approved  by  R.  Koch  in  his  intro- 
duction when  he  says  that  "it  is  not  advisable  continuously  to 
give  only  the  smallest  doses,  as  recommended  in  many  quarters. 
It  must  not  be  forgotten  that  it  is  a  question  here  of  active  immu- 
nization, and  that  it  can  only  be  of  advantage  to  the  patient  that 
not  too  low  a  degree  of  immunity  should  be  attained." 

,_      .  .  .  -    The  first-named  method — the  exclusive  use 

Exclusive  Use  of  ,,         ,     .  „         , 

or    small  and  the  smallest   doses — has   not 

^^  KYI  r\  I  I         IJ  A^pq 

_  been  able  to  produce  any  valid  reasons  to 

Not  Justified,  justify  its  existence.  Nourney  injects  only 
the  smallest  doses  at  long  intervals,  in  order  to  produce  and 
maintain  "  Tuberculin  Energy."  His  is  a  somewhat  isolated 
position.  Wright's  method,  which  he  built  up  into  a  system  of 
±iis  own,  rests  on  the  same  principle  of  treatment  and,  as  has 
already  been  stated,  is  being  more  and  more  abandoned.  The 
continuance    of    the    smallest    doses    is    not 

OWing     tO  rr  •  1-1111 

.  very    effective   and    easily   leads    to    hyper- 

Production  of  SUSceptibility.  We  have  already  explained 
Hypersusceptibihty.  that,  according  to  our  experience,  the  pro- 
duction of  hypersusceptibihty  in  the  course  of  tuberculin  treat- 
ment has  never  been  of  advantage  to  the  patient  and  that  the 
essential  nature  of  hypersusceptibihty  is  not  sufficiently  under- 
stood to  justify  such  far-reaching  conclusions  as  to  the  therapeutic 
use  of  tuberculin. 

In  support  of  our  standpoint,  we  would  like  to  call  attention 
to  the  experiences  of  the  Leipzig  Medical  Clinic,  given  lately  by 
Roily  [160].  Two  hundred  patients  were  treated  at  intervals  of 
from  five  to  eight  days  with  the  smallest  doses  of  old  tuberculin, 
beginning  with  "ooi  c.mm.,  and  going  up  to  "oi  c.mm.  The 
hypersusceptibihty  which  regularly  ensued  prevented  the  dose 
ever  being  increased  beyond  o'l  c.mm.  The  only  good  result  was 
a  generally  appreciable  increase  in  weight ;  an  objective  improve- 
ment in  the  condition  of  the  lung  was  not  attained  to  such  a 
degree  as  to  justify  the  assumption  that  the  tuberculin  had 
exercised  a  definite  curative  influence. 


THE   SPECIFIC  TREATMENT  OF  TUBERCULOSIS  1 47 

_  On  the  other  hand,  some  recently  published 

Penzoldts  Results  statistics  of  penzoldt  [161]  speak  in  favour 

with   Large,  Q£   jarge   doses   used   with   caution,    and   to 

Cautious  Doses.     these    we    should    like    to    draw    attention. 

They  date  from  the  first  tuberculin  era. 

Nineteen  years  ago  Penzoldt  treated  ten  cases  of  tuberculosis  of  various 
stadia  with  large,  carefully  increased  doses  of  tuberculin.  Of  these 
patients  two  died  after  fifteen  to  sixteen  years,  one  from  a  relapse,  the 
other  from  an  unknown  cause.  Of  the  others  only  one  underwent  later  a 
second  cure,  and  all  enjoy  to-day  a  satisfactory  or  even  good  state  of  health 
quite  equal  to  the  demands  of  their  calling,  in  some  cases  very  severe 
demands.  One  of  these  cases  Penzoldt  had  expected  to  prove  fatal. 
Penzoldt  demands  that  statistics  should  continue  to  be  kept  of  such  cases 
of  tuberculin  treatment  as  have  been  under  observation  for  many  years, 
so  as  to  prove  which  is  the  best  method  of  using  tuberculin. 

.  ,  ,        With  regard  to  the  action  of  tuberculin,  a 

Avoidance  ot         ,.  ,.     ,.  ,     ,  ,      ,    ,  ., 

distinction     must     be     made     between     the 

Reaction.  general  reaction  of  the  whole  organism  and 

the  local  reaction  of  the  diseased  focus.  In  the  mild  method  of 
injection  they  only  occur  in  a  very  much  weakened  form  and  it 
must  be  the  aim  to  avoid  severe  reactions  as  far  as  is  possible. 
The  view  must  be  entirely  put  on  one  side  that  the  curative  process 
in  tuberculin  treatment  takes  place  only  with  objective  signs  of 
reaction.  Clinical  observation  in  cases  of  lupus  and  of  laryngeal 
tuberculosis  teaches  that  a  local  effect  on  the  focus  of  disease  may 
make  itself  evident  by  hyperemia  without  a  subjective  feeling  of 
illness  or  appreciable  rise  of  temperature.  The  more  gently  the 
treatment  is  carried  through,  the  slighter  will  be  the  evidence  of 
local  and  general  reaction.  General  toxic  symptoms  may  occur 
with  or  without  rise  of  temperature ;  these  are  tiredness,  pains  in 
the  limbs  and  loss  of  appetite,  and  even  in  the  absence  of  fever 
these  are  to  be  construed  as  a  specific  reaction.  It  is  well  to  treat 
them  as  equivalent  to  a  febrile  reaction  and  to  repeat  the  previous 
dose  of  tuberculin,  when  recurrence  of  the  symptom  is  as  unusual 
as  a  repetition  of  the  fever.  The  conception  of  the  tuberculin 
reaction  must  be  wider  than  the  one  in  current  use. 

With  sufficient  care  it  will  then  be  possible  in  the  majority 
of  cases  to  carry  through  a  course  of  tuberculin  treatment  to  a 
finish  without  appreciable  rise  of  temperature  and  without 
damaging  the  general  health.  But  the  susceptibility  to  tuber- 
culin varies  in  different  individuals,  and  treatment  must  therefore 
be  strictly  individualistic. 

Observation    of  The   more   carefully  doctor   and   patient   watch   the 

Temoerature  ■  symptoms,  the  more  easily  will  the  course  of  treat- 

'  ment    run    without    undesired    interruptions.       The 

common     practice     of  observing     the     temperature     curve     only     is     quite 


I48  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

insufficient   for  the  purpose.        The  effect  of  the  tuberculin   on  the   general 
health  must  also  be  carefully  considered  and  noted. 

It  is  advisable  to  carry  out  the  observations  of  a  case  as  follows  :  Each 
patient  takes  his  temperature  every  two  or  three  hours,  preferably  the  former, 
and  enters  the  observation  in  the  form  of  a  curve.  The  fever  limit  is 
37'3°  C.  taken  in  the  mouth;  and  the  reading  taken  in  the  manner  usual  in 
sanatoria  and  with  the  necessary  precautions  may  be  regaided  as  absolutely 
trustworthy.  Temperature  not  to  be  taken  in  the  open  air  during  cold 
weather.  The  patient  is  instructed  to  go  to  bed  if  this  limit  is  appreciably 
exceeded  or  if  he  feels  ill.  Otherwise  exercise  suitable  for  his  condition 
may  be  taken,  and  in  any  case  confinement  to  bed  is  unnecessary.  Any 
symptoms  are  to  be  noted  by  the  patient  on  his  chart,  so  that  the  influence 
of  any  particular  injection  on  temperature  and  general  health  can  be  noted 
at  a  glance.  This  method  applies  specially  to  sanatoria,  hospitals  and  out- 
patient practice,  where  a  considerable  number  of  patients  attend  for 
injection.  In  some  few  cases  a  special  inquiry  after  symptoms  will  be 
necessary. 

,     ,.  As  a  control  the  observation  of  the  body- 

of  other  J  , 

weight  is  01  importance,  and  in  some  cases  01 

oymptoms  .         thepulse.  Loss  of  weight  and  sudden  increase 

Loss  of  Weight  ;     -m   frequency  of  a  normal  pulse  are  to  be 

construed  as  the  expression  of  an  overdose  of  toxin,  in  the  absence 

of  other  obvious  cause.     This  overdose  of  toxin,  as  a  rule,  finds 

its  expression  in  a  hypersusceptibility  to  tuberculin,  but  it  may 

also  occur  without  fever.     In  any  case,  the  occurrence  of  loss  of 

weight    must    be    carefully    considered,    and    when    it    occurs    no 

increase  of   the   dose   is   permissible.      It   is   advisable   rather  to 

increase  the  intervals  or  even  return  to  a  smaller  dose,  until  the 

appetite,  and  with  it  the  weight,   improves  again.     In  the  same 

way  the  behaviour  of  the  pulse  is  to  be   used  as  a  control ;   a 

marked  increase  in  the  pulse-rate  after  an  injection  of  tuberculin 

is  an   unfavourable  symptom  and  demands  caution.      The  next 

._  r        injection  is  to  be  delayed  until  the  return 

r reojuency  ot 

p.  °f  tne  pulse-rate  to  the  normal,   which,   as 

a  rule,  takes  place  in  one  or  more  days. 
It  must  then  not  be  a  larger  one,  and  pulse  and  dosage  should 
thereafter  be  watched  with  particular  care.  With  an  unstable 
pulse  an  overdose  of  toxin  must  be  constantly  before  the  mind. 
On  the  other  hand,  we  also  see  the  accelerated  pulse,  which  is  so 
frequent  a  consequence  of  the  absorption  of  toxins  of  the  tubercle 
bacilli,  become  gradually  slower  in  the  course  of  tuberculin  treat- 
ment. We  have  repeatedly  observed  a  pulse-rate  of  120  in  the 
minute  steadily  fall  to  80  in  the  course  of  six  months  (Chart  18). 
This  is,  however,  not  easily  obtained,  generally  only  by  pro- 
longed treatment  with  tuberculin. 

The  observance  of  symptoms  must  also  be  supplemented  bv 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS  1 49 

physical  examination  of  the  chest,  its  frequency  of  repetition  being 
guided  by  the  severity  of  the  case  and  the  course  of  the  treatment 
and  the  result  carefully  recorded  for  the  purpose  of  comparison. 

For  correctly  estimating  the  individual  susceptibility  to 
tuberculin,  more  attention  must  be  paid  to  the  relative  than  the 
absolute  rise  of  temperature.  The  control  of  the  temperature  is 
of  the  greatest  importance  in  tuberculin  treatment. 

Registration    of       ^   *s  a^visa^le   t0   register  the  temperature   in  the 
form  of  a  curve.     The  waves  in  the  curve  in  their 
I  emperature.  relation  to  each  other  are  of  more  importance  than 

the  actual  elevation  by  so  many  tenths ;  and  their  observation  is  essential  if 
the  limit  of  reaction  is  to  be  approached  as  closely  as  possible.  It  is  then 
much  easier  to  judge  when  even  a  slight  rise  begins,  reaches  its  acme  and 
ends;  and  so  to  decide  on  the  necessary  interval,  varying  from  case  to  case, 
and  in  so  doing  avoid  the  possibility  of  cumulative  action.  We  therefore 
warn  against  taking  the  temperature  only  twice  a  day,  and  regard  at  least 
five  times  as  necessary  (at  8,  11,  2,  5,  and  8  o'clock).  In  ambulant  practice 
it  should  be  taken  at  least  four  times  (8,  12,  4,  and  8  o'clock).  No  ambulant 
treatment  without  measurement  of  temperature  ! 

~  £       The  slightest  rise  of  temperature  must  have 

Occurrence  ot 

subsided  before  the  next  injection  is  given. 

°  The  dose  must  be  the  same  as  the  previous 

one  and  only  be  raised  after  the  temperature 
curve  becomes  quite  normal.  The  behaviour  of  the  temperature 
curve  after  the  first  injections  is  characteristic  of  the  whole  course 
and  is  therefore  important  for  regulating  the  injections  and 
dosage.  But  a  sensitive  temperature  may  occur  onlv  at  the  begin- 
ning of  the  course  and  soon  disappear  with  correct  technique, 
in  the  same  way  as  slight  fever  may  often  be  got  rid  of  by  con- 
tinued repetition  of  slight  reactions. 

A .  ,  The  maxim  to  remain  as  close  as  possible 

Aim    TO     Kppn  ^ 

,  .     .        .    to  the  reaction  limit  without  well-marked  or 
near  the  Limit  of  ,.  .     .  ,  ... 

severe    reactions    occurring    coincides    with 

action.  the  experience  that  the  most  evident  success 

has  been  obtained  with  slight  reactions  up  to  380  C,  or  a  little 

over.     There  is,  on  theoretical  grounds,  nothing  to  be  said  against 

this  if  proper  precautions  and  oversight  are  observed,  although 

the  production  of  these  slight  reactions  is  by  no  means  always  to 

be   ens'ured.      The   method    will   be   more   successful    with    some 

experience   of  tuberculin    treatment.      The    beginner    should    lav 

special  stress  on  the  avoidance  of  reaction.     Its  practicability  will 

also  depend  on  the  individual  susceptibility  to  tuberculin,  on  the 

severity  of  the  disease,    and   on   the   general   constitution.      The 

principle  of  the  production   of  slight   reactions  will  be  more   in 


150  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

place  and  easier  to  carry  out  in  slighter  and  more  limited  cases  of 

disease,  in  the  slowly  progressive  forms  associated  with  fibrosis, 

where  nutrition  and  appetite  are  good,  where  weight  is  being  put 

on  and  the  temperature  normal  and  where  the  susceptibility  to 

tuberculin    is   slight.      But    in   these   cases   the  possibility  of   an 

overdose  must  still  be  borne  in  mind. 

_  ,     .        «    ..        We     now     come    to     the    most     important 

Cumulative  Action        •   ,  •     ,  t  ,•  t        ,     ^1 

point  in  tuberculin  treatment — the  question 

and   Mypei-  Q£  cumuiative  action  and  of  hypersuscepti- 

susceptibility.        bility  to  the  toxin.     It  is  only  possible   in 

the   rarest   cases   to   fulfil    the   demand   to   avoid   febrile   reaction 

altogether.       Observing    all    precautions,    fever    will    sometimes 

occur  after  an  injection,  which  may  last  one  or  more  days  or  even 

over  a  week.     A  pause  of  several  days  must  then  be  made  after 

the  temperature  has  fallen,  and  the  same  dose  then  repeated.     As 

a  rule  this  repetition  causes  no  further  rise  of  temperature,  or  at 

any  rate  a  slighter  one  ;  in  the  latter  case  the  same  dose  should 

again  be  repeated,   if  necessary  even  a  third  time.     But  it  may 

also  happen  that  the  repetition  of  the  same  dose  gives  rise  to  a 

higher     febrile     reaction     than     the     first.       This     characteristic 

,^.  A.  phenomenon    was    described    by    Koch    in 

Diagnostic  ^         .  ..  .•••.■  ,-  '    1  ,- 

regard  to  diagnostic  injection  01  tuberculin 

oigni  icance  o        an(^    -^   significance    in    diagnosis    utilized. 

Cumulative  Actions.  ^  cumulative  process  was  assumed,  the  rise 

of  temperature  being  merely  the  expression  of  a  summation  of 

successive  toxic  effects.     More  modern  is  the  explanation  of  the 

occurrence     by     a     toxic     hypersusceptibility.       This     plausibly 

assumes  an  increased  susceptibility  due  to  too  rapid  increase  of 

dosage,    deliberately    aimed    at    within    prescribed    limits    in    the 

diagnostic  application  ;  in  other  words,   it  is  due  to  an  overdose 

of  toxin.        In  tuberculin  treatment  the  occurrence  is  altogether 

unwelcome  and  the  most  frequent  cause  of  harm.     If  it  is  not 

.  .         .  sufficiently   recognized   and   allowed   for,    a 

Unwelcomeness      <•,,•,  1,  1 

further    reactionless    course    will     not     be 

in  Treatment.  attained  :  the  continued  repetition  of  the 
same  dose,  or  a  too  tardy  return  to  a  smaller  one,  will  only  con- 
tinue to  produce  severe  febrile  reaction  and  may  lead  to  actual 
harm.  In  such  a  case  it  is  best  to  allow  a  pause  of  eight  or  even 
fourteen  days,  to  recommence  with  a  much  smaller  dose  and  to 
proceed  with  redoubled  slowness  and  caution.  If  the  interpreta- 
tion of  the  term  reaction  is  the  wider  one  already  alluded  to, 
including  not  merely  the  rise  of  temperature  but  other  objective 
and  subjective  symptoms,  it  will  generally  be  possible  to  recog- 
nize and  prevent  a  threatening  cumulation  and  overdose  of  toxin. 


THE   SPECIFIC   TREATMENT  OF   TUBERCULOSIS  I5I 

For  the  time  of  injection  we  recommend,  at 
Time  o  variance  with  some  other  authors,  the  morn- 

Injection.  ing    and    not    the    ^.^-,1,^     sinCe    febrile 

reaction  of  moderate  degree  may  occur  unnoticed  during  sleep 
and  leave  no  trace  on  the  following  morning,  with  the  result 
that  the  next  increase  in  the  dose  may  give  rise  by  cumulation 
to  high  fever. 

.  .  The  interval  between   successive   injections 

Interval  between     wm    be    gQnq    [ntQ    more    fuUy    when    the 

Injections.  several    tuberculin     preparations     are     dis- 

cussed. It  need  only  be  said  here  that  the  original  method  of 
giving  a  dose  daily,  which  still  has  some  vogue,  is  inconsistent 
with  the  mild  reactionless  method,  since  even  febrile  reaction  may 
not  make  itself  felt  for  twenty-six  to  thirty  hours.  Besides  this, 
we  know  from  experience  with  other  immunizing  methods  that 
the  organism  requires  a  certain  time  for  production  of  antitoxic 
substances  after  assimilation  of  toxin.  The  length  of  this  incu- 
bation period  varies  for  different  toxins  and  is  not  definitely 
known  for  tuberculin,  but  practical  experience  of  the  summation 
of  reactions  indicates  that  daily  injection  is  too  frequent  for  even 
the  small  tuberculin  doses.  Analogy  leads  to  the  further  con- 
clusion that  with  increasing  dosage  the  interval  must  be  length- 
ened. 

"        .  In     considering    the    maximal    therapeutic 

Maximal  ,  ,..•.•  r         u  a 

dose,    a    distinction    must     first    be    made 

Uose.  between  the  absolute  maximum,  which  will 

be  considered  under  the  several  preparations,  and  the  maximum 
for  the  individual.  It  must  be  the  aim  to  approach  the  absolute 
maximal  dose  as  nearly  as  possible  in  every  individual  case.  But 
this  must  not  lead  to  hurrying  with  the  injections  or  the  increasing 
dosage  in  order  to  complete  the  course  in  a  given  time.  It  must  be 
constantly  kept  in  mind  that  the  curative  effect  for  the  individual 
is  dependent  not  on  the  absolute,  but  on  the  relative  size  of  the 
dose,  i.e.  that  quantity  of  tuberculin  is  most  advantageous  which 
can  at  any  time  just  be  borne  without  reaction.  This  considera- 
tion is  the  likeliest  to  prevent  the  beginner  from  proceeding  too 
rapidly  with  the  dosage  in  the  natural  endeavour  to  provide  the 
diseased  organism  with  the  maximum  amount  of  antibodies.  It 
must  not  be  forgotten  that  in  active  immunization  there  are  no 
ready-made  antibodies  for  the  patient  to  assimilate,  but  they  must 
first  be  produced  with  the  help  of  the  toxins  introduced.  Rapid 
increase  has,  then,  on  the  one  hand,  no  curative  value;  on  the 
other,  the  occurrence  of  severe  reaction  may  affect  the  patient's 
general  health,   reduce  his  power  of  resistance  for  some  or  all 


152  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

time,   and,   by  producing  hypersusceptibility,   may  stand  in   the 

way  of  the  continuance  of  the  course.     With  this  knowledge  the 

desire  to  complete  the  course  within  a  specified  time  will  not  make 

us  move  from  the  prescribed  lines.     If  in  such  a  case  the  period 

of    treatment    cannot    be    extended,     it    is 

°  _  always  better  to  reach  a  smaller  dose  with- 

be  Hurried.  out    reaction    than    t0    attempt    to    attain    a 

higher  one  by  violence. 

The. same  applies  to  any  very  susceptible  patient,  no  matter  in 

what  stage  of  disease ;  it  is  not  so  much  a  question  of  laboriously 

attaining  a  certain  dose  of  tuberculin,  as  to  ensure  the  assimilation 

of   the   doses   given    without   undue   exertion    for   the   organism. 

Hence  time  must  be  allowed  for  the  increase  of  dosage ;  the  same 

dose  repeated,  if  necessary,  several  times  if  reaction  occurs,  with 

increase  of  the  interval ;  or,  better,   a  return  made  to  a  smaller 

dose,    increased  again   still  more  slowly.     The  thought  guiding 

the  technique  must  be  that  any  dose  associated  with  fever  is  too 

high  for  the  individual  concerned  and  that  the  smaller  dose,  borne 

without  reaction  not  merely  suffices  for  therapeutic  action,  but  is 

actually  of  more  value.     And  to  this  view  one  must  adhere  when 

obliged  for  months  to  use  only  thousandths  and  hundredths  of 

cubic  millimetres,  and  when  the  end-dose  perhaps  does  not  exceed 

1  c.mm.     Tolerance  cannot  be  attained  by  violence,  but  .only  by 

patiently  persisting.     Such  grades  of  tuberculin  susceptibility  are, 

however,   not  common  ;  they  have  been  discussed  thus  fully  on 

account  of  the  greater  difficulty  in  their  treatment. 

These  considerations  lead  us  to  the  question 
Inadequacy  of         ,  .  ~.  .  1  , 

^        '  whether   it   is   not   sufficient  or  even   better 

Minute  Doses.  to  be  content  with  small  doses  of  tuberculin 
or  whether  larger  doses  are  the  goal  to  be  reached.  We  adhere 
to  the  principles  enunciated  by  Koch  for  the  several  tuberculin 
preparations.  If  the  basis  of  the  modern  view  is  accepted,  that 
one  aspect  of  the  action  of  tuberculin  rests  on  a  systematically 
acquired  tolerance,  a  gradually  acquired  immunity  to  the  toxin, 
then  the  employment  of  larger  doses  of  tuberculin  cannot  be 
dispensed  with.  And  after  what  'has  been  said  it  is  clear  that 
with  this  theoretical  view  the  practical  carrying  out  of  a  reaction- 
less  course  of  treatment  is  quite  reconcilable. 

.         il       r  We  now  turn  to  the  question,  how  long  the 

Length  of  .      1  ,.    n  ,       ,  ,   , 

course  of   tuberculin   treatment   should   last 

and   with   what   final   dose   to   end?       The 

onlv  answer  of  universal  application  would  be — until  the  patient  is 

cured,   or  as  long  as  improvement  continues.       But  it  must  be 

borne  in  mind  from  the  outset  that  the  duration  of  treatment  is  in 


THE   SPECIFIC   TREATMENT  OF   TUBERCULOSIS  1 53 

most  cases  neither  in  the  command  of  practitioner  nor  of  patient. 
Distinction  must  first  of  all  be  made  as  to 
In  banatonum  ,  wnether  the  treatment  is  in  a  sanatorium  or 
in  general  practice.  In  Germany  the  conditions  in  regard  to 
tuberculosis  among  the  working  classes  are:  Members  of  that 
section  of  the  community  in  which  compulsory  insurance  holds 
must,  when  the  condition  of  the  lung  is  curable  or  capable  of 
substantial  improvement,  be  brought  for  a  limited  time  into  a 
sanatorium  or  health  resort  and  a  cure  effected  in  this  time.  The 
severer  cases  and  those  for  whom  insurance  is  not  compulsory 
remain  under  treatment  by  the  general  practitioner,  or  in  some 
cases  are  treated  for  a  while  in  hospital  or  in  some  voluntary 
institution. 

In     private     practice     the     conditions     are 
In   Private,  similar  :    The    stay    in    the    sanatorium    is 

mostly  a  limited  one,  much  too  short  to  attain  a  complete  cure; 
the  patients  return  for  treatment  by  their  home  doctor.  In  only 
relatively  few  cases  is  the  patient  in  a  position  to  complete  his 
cure  in  a  sanatorium  or  health  resort  under  the  eye  of  the  one 
physician.  All  this  must  be  considered  with  the  question  of  the 
duration  of  tuberculin  treatment.  We  must  expressly  emphasize 
here  that  we  regard  the  treatment  of  active  tuberculosis  of  the 
lung  as  a  matter  for  the  sanatorium,  and  tuberculin  treatment  as 
an  essential  part  of  sanatorium  treatment  in  the  majority  of 
severer  cases. 

A .  .It   must  be   our   aim   to   reach   the   highest 

Aim  to  reach  -,  ,      ,  r  .•  •       1 

possible   doses  of  tuberculin,    to  attain   the 
Maximal   Dose.       maxima]  dose.     In  s]ight  cases  a  cure  wi]l 

be  effected  in  this  way.  If  the  limit  of  apparently  possible 
improvement  is  not  then  reached,  the  maximal  dose  is  to  be 
repeated  at  increasing  intervals  of  8,  10,  and  14  days,  as  long  as 
improvement  continues,  in  order  to  retain  the  toxic  immunity  as 
long  as  may  be,  to  stimulate  the  production  of  antibodies  and  to 
assist  the  healing  processes.  This  injection  of  the  absolute  maxi- 
mum we  have  ourselves  prolonged  for  many  months  in  severe 
cases. 

Weddy-Poenicke  has  lately  recommended  as  the  result  of 
his  own  experience  the  prolongation  of  the  intervals  to  three, 
four,  and  finally  six  to  eight  weeks,  and  believes  that  even  breaks 
of  three  and  more  months  would  be  possible  and  sufficient.  We 
ourselves  [162]  have  used  this  method  of  the  injection  of  large 
doses  at  intervals  of  four  to  six  to  eight  weeks  .with  T.R.  for 
many  years. 

The  above-mentioned  discoveries  by  Lowenstein  and  Pickert 


154  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

of  the  neutralizing  substances  proved  by  them  to  exist  in  the 
serum  and  to  be  looked  upon  as  antibodies  to  tuberculin,  also 
point  to  the  expediency  and  necessity  of  large  doses  of  tuberculin. 
After  injections  of  large  doses  of  tuberculin,  they  observed  the 
same  regular  phases  taking  place  in  the  antibodies  of  the  serum 
as  in  other  processes  of  immunization.  In  consideration  of  the 
curve  of  the  tuberculin  antibodies,  Pickert  [18]  insists  on  intervals 
of  at  least  fourteen  days  in  the  injection  of  large  doses  of  tuber- 
culin in  order  to  maintain  the  quantity  of  antibodies  at  a  suffi- 
ciently high  level  to  be  favourable  to  the  organism. 

If  susceptibility  does  not  permit  of  the  absolute  maximum 
being  arrived  at,  the  individual  maximal  dose  should  be  repeated 
and  the  attempt  persisted  in  to  raise  the  dose  when  possible  still 
further,  an  attempt  which  may  at  any  time  succeed. 

The  further  question  must  now  be  answered, 
After-treatment.      what  tQ  do  with  the  patient  wj10  js  not  yet 

cured  when  his  time  in  the  sanatorium  has  expired.  The  logical 
outcome  of  what  has  been  said  is  the  continuance  of  his  tuberculin 
treatment  at  home.  The  fulfilment  of  this  demand  assumes  that 
tuberculin  should  find  its  way  widely  into  general  practice.  And 
there  can  be  no  doubt  that  it  would  be  productive  of  untold  good 
if  every  practitioner  were  to  master  the  technique  of  tuberculin 
administration  and  employ  it  wisely.  The  whole  aspect  of  the 
struggle  against  tuberculosis  would  then  be  altered. 

Sahli  [163],  too,  has  recently  advanced  the 

view  that  tuberculin  treatment  is  properly  a 

matter  for  the  family  doctor,   and  has  expressed  his  conviction 

that  tuberculin  is  destined  to  play  a  beneficent  role  similar  to  that 

of  vaccination  in  small-pox. 

He  [164]  adopts  an  extreme  point  of  view  in  so  far  as  he 
stands  for  the  principle  of  the  mildest  tuberculin  treatment  with- 
out the  slightest  objective  and  subjective  reaction  and  looks  upon 
all  methods  which  seek  to  obtain  a  manifest  reaction  as  cutting 
both  ways  and  dangerous.  He  continues  the  treatment  for  a 
very  long  period,  sometimes  several  years.  He  does  not  wish  to 
obtain  regular  immunity,  but  only  an  immunizing  curative  effect. 
He  describes  as  the  goal  of  the  active  immunizing  treatment 
immunization  to  toxins,  that  is  "  the  production  of  curative  im- 
munizing reactions  by  substances  of  little  or  no  toxicity.  These 
specific  toxoid-like  substances  should  possess  the  same  haptophore 
groups  as  the  corresponding  toxins,  but  should  be  as  free  as 
possible  from  the  toxophore  groups  which  characterize  these 
toxins."  A  very  similar  conception  has  lately  been  taken  up  by 
Vaughan  [165]. 


THE   SPECIFIC   TREATMENT  OF   TUBERCULOSIS  155 

Where  a  cure  is  not  attained  with  the  single  course  of  treat- 
ment and  the  prolongation  of  the  injections  in  the  manner 
described  is  impracticable,  the  question  must  be  considered 
whether  a  repetition  of  the  course  is  in  place,  and  if  so,  when. 
Definite  rules  cannot  be  laid  down  here.  It  will  be  advisable 
from  time  to  time  to  test  the  susceptibility  to  tuberculin,  taking 
this  as  a  criterion  of  the  measure  of  cure  reached. 

_     .   ,  A  systematic  method  has  been  evolved  by 

Serial 

Petruschky     [166]     with     his     interrupted 

Treatment .  treatment ;     in     this    method    the    average 

Petruschky.  duration     of    treatment    necessary     is    two 

years,  periods  of  two  to  three  months  during  which  injec- 
tions are  given  alternating  with  pauses  of  three  to  four  months. 
Petruschky  [167]  records  "  how  Koch  strained  every  nerve- 
evolved  new  tuberculin  preparations,  increased  the  duration  of 
treatment  and  gave  enormous  doses — in  order  to  ensure  a  cure  in 
a  single  period  of  treatment,  knowing  full  well  how  difficult  it  is 
to  get  hold  again  of  a  discharged  patient.  The  result,  however, 
was  unsatisfactory,  at  any  rate  as  a  rule."  Experiences  such 
as  these  gradually  led  Petruschky  to  the  systematic  working  out 
of  his  interrupted  treatment. 

_   .x.  .  j.  ±l  .       We    find    ourselves     in     no     irreconcilable 

Criticism   of  this  .      ,  ,       ,  •  ^, 

attitude    towards    this    system.      Charts    13 

and  14  illustrate  just  such  a  method  with 
two  periods  of  treatment,  but  they  show  also  the  different  con- 
ception of  duration  of  treatment  and  dosage  which  we  hold.  It 
is  only  natural  that  the  sanatorium  doctor,  in  common  with  all 
those  in  charge  of  in-patients,  should  seek  to  extend  the  first 
period  of  treatment  as  long  as  he  is  in  a  position  to  obtain  any 
considerable  improvement  of  the  physical  signs  in  the  lung.  But 
it  cannot  seriously  be  contended  that  the  utmost  attainable  in 
the  first  period  of  tuberculin  treatment  is  really  reached  by 
Petruschky's  maximal  dose  of  50  to  100  c.mm.  of  old  tuberculin, 
or  o'i  c.mm.  of  new.  Such  a  final  dose  may  suffice  for  a  case 
of  tubercular  glands  in  a  child  or  for  one  of  closed  tuberculosis 
in  its  slightest  form,  if  the  patient  can,  as  in  Petruschky's  case, 
be  kept  permanently  under  control  and  undergo  at  anv  time  one 
or  more  further  periods  of  treatment.  But  the  sanatorium  doctor 
will  be  as  little  able  to  attain  this  with  the  patients  of  the  insurance 
and  friendly  societies  under  the  present  regime  as  with  private 
patients  on  economic  grounds.  But  in  all  cases  of  open  tubercu- 
losis, as  well  as  in  all  advanced  forms,  the  curative  effect  of 
tuberculin  is  by  no  means  exhausted  with  the  maximal  doses  used 
by  Petruschky.     Our  own  prolonged  clinical  experience  teaches 


156  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

ever  afresh  that  permanent  success  increases  with  the  duration  of 
treatment.  All  the  examples  in  the  temperature  curves  in  this 
book  show  that  the  sputum  does  not  disappear  for  a  period  of 
months  with  large  doses  of  tuberculin,  and  these  are  typical  cases. 
We  cannot  therefore  recommend  breaking  off  the  tuberculin 
treatment  in  cases  of  the  II  and  III  Stadia  at  such  low  doses 
and  postponing  the  continuation  to  a  future  time,  quite  apart 
from  the  fact  that  the  incompletely  cured  patient  is  exposed  to  all 
manner  of  intercurrent  affections.  In  their  demand  for  the  use 
of  large  doses  of  tuberculin,  Engel  and  Bauer,  as  already  men- 
tioned, go  much  further  than  we  do,  on  the  ground  of  new  re- 
search and  clinical  successes  in  the  treatment  of  tuberculosis  in 
young  children  in  the  Dlisseldorf  Children's  Hospital.  They 
were  able  to  prove  that  with  the  quantity  of  tuberculin  injected, 
the  number  of  antibodies  in  the  blood  increased,  and  that  all 
patients  with  a  good  quantity  of  antibodies  made  satisfactory 
progress  and  showed  an  appreciable  retrogressive  metamorphosis 
of  the  tubercular  process.  Also  Jochmann  and  Mollers  have  re- 
cently proved  that  complement-fixing  antibodies  only  appear  in 
the  serum  when  large  doses  are  reached. 

In  a  recent  extensive  treatise  on  the  tuberculin  treatment  of 
pulmonary  tuberculosis,  Petruschky  [168]  has  again  revived  his 
method  and  compares  it  with  our  own.  Although  he  does  not 
entirelv  agree  with  our  view  as  to  maximal  dose  and  the  treatment 
of  hypersusceptibility,  he  agrees  with  us  in  the  frequent  necessity 
for  the  larger  doses  and  the  individualizing  dosage  according 
to  the  sensitiveness  or  insensitiveness  of  the  patient  in  question. 
He  rightly  asserts  that  large  doses  need  not  always  be  reached, 
but  expressly  demands  that  there  must  be  no  kind  of  limitation 
in  respect  of  the  duration  or  final  dose  of  the  first  period  of 
treatment  nor  of  the  subsequent  periods.  Therefore,  though  we 
do  not  on  principle  exclusively  recommend  tuberculin  treatment 
by  the  interrupted  method,  we  agree  with  him  in  setting  the 
greatest  store  on  the  first  period  of  treatment  reaching  the  maxi- 
mum attainable. 

...  c      We   do    not   bv   any    means    underestimate 

After-history  of  .  -         -  ...     .    ,  ,. 

.  or   neglect  after-treatment  with   tuberculin. 

uberculin-  j^Q  experience  of  our  systematic  investiga- 

treated   Patients.     t;on  jnt0  after-histories  shows  only  too  well 

that  the  struggle  for  existence  often  prematurely  annihilates  the 

good  done  by  treatment.     After-treatment  with  tuberculin  would 

doubtless  avoid  this   in   many  cases.     Therefore    we    want    the 

assistance    of   practitioners    in    continuing    in    ambulant    practice 

specific  treatment  commenced  in  a  sanatorium  or  recommencing 


THE   SPECIFIC   TREATMENT  OF   TUBERCULOSIS  157 

it  when  necessary.  All  seemingly  healed  patients  must  from  time 
to  time  be  examined  and  tested  to  show  whether  their  subjective 
or  objective  symptoms  are  such  as  to  demand  after-treatment. 
This  after-treatment  is  also  to  be  instituted  in  all  severe  forms 
of  tuberculosis  in  which  cure  has  not  followed  a  single  period 
of  treatment.  Whether  the  continuous  repetition  of  the  maximal 
dose  already  described  or  a  repetition  of  the  whole  course — in 
one  or  several  periods — is  desirable,  must  be  decided  in  each 
particular  case.  Anyhow,  small  doses  will  not  suffice  in  severe 
cases  for  the  repetitions  either ;  we  are  here  in  complete  agreement 
with  Kraemer  [169]  that  the  after-treatment  (cf.  Chart  14)  should 
reach  the  individual  maximal  dose. 

We    will    refer    here    to    a    recent    work    of 
Value  o  ^  Schroder  [170],   in  which  he  expresses  his 

Tox-i mm  unity.  disagreement  with  our  therapeutic  principle 
of  the  tox-immunity  of  the  tubercular  organism  by  high  doses  of 
tuberculin.  We  have  sufficiently  shown  the  theoretical  founda- 
tion of  our  standpoint  and  we  shall  shortly  show  that  this  system 
of  treatment  has  proved  the  best  in  actual  practice.  Schroder 
asserts  that  patients  who  have  attained  tox-immunity  are  liable 
to  severe  relapses.  We  cannot  leave  this  uncontradicted. 
Although  in  most  of  the  cases  quoted  there  is  no  question  of 
high  immunity  at  all,  the  experiences  met  with  in  a  small  pro- 
portion of  the  cases  do  not  justify  the  generalization  of  such  a 
verdict.  As  far  as  we  know,  Schroder  has  never  made  personal 
trial  of  our  method.  But  there  should  surely  be  no  one  who  has 
had  more  experience  of  it  than  we  ourselves ;  and  we  can  testify 
that  in  our  cases  so  treated  we  have  never  observed  severe  relapses 
in  any  striking  proportion.  On  the  contrary,  we  have  often 
enough  witnessed  changes  for  the  worse  just  in  those  cases  where 
tuberculin  treatment  could  not  be  sufficiently  prolonged  owing  to 
external  considerations. 

Jochmann  [171],  who  in  general  adopts  the  same  standpoint 
as  ours — that  the  length  of  tuberculin  treatment  must  depend 
"  solely  and  entirely  on  the  sum  of  the  biological  and  clinical 
criteria  " — thinks  that  the  disappearance  of  the  cutaneous  re- 
action, with  favourable  clinical  conditions,  may  be  considered  as 
an  indication  for  the  cessation  of  the  tuberculin  treatment  and, 
on  the  other  hand,  the  reappearance  of  the  reaction  on  a  sub- 
sequent test  after  some  months  as  an  indication  for  the  beginning 
of  the  after-treatment.  He  therefore  replaces  Petruschky's  sub- 
cutaneous after-test  with  the  cutaneous  test  which  biologically  is 
essentially  the  same.  There  is  only  a  quantitative  distinction  to 
be  made  between  the  two  methods ;  to  us  the  clinical  after-test 
seems  the  most  important  and  decisive. 


158  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

The  question  also  of  the  cessation  of  the  first  tuberculin  cure 
when  v.  Pirquet's  test  becomes  negative  requires  to  be  more 
carefully  considered,  jochmann  recommends  previous  treatment 
with  old  tuberculin  up  to,  perhaps,  300  to  500  c.mm.,  until  the 
skin  fails  to  react  to  the  test  made  with  old  tuberculin.  At  this 
time  there  is  always  a  positive  cutaneous  reaction  to  bacillary 
emulsion.  So  treatment  with  bacillary  emulsion  must  follow 
until  the  skin  fails  to  react  to  this  preparation  also.  But,  accord- 
ing to  our  investigations,  undertaken  quite  independently,  this 
often  happens  with  undiluted  bacillary  emulsion  at  a  time  when 
the  presence  of  tubercle  bacilli  can  still  be  proved  in  the  sputum. 
We  have  observed  this  even  after  therapeutic  doses  of  from 
o"5  to  ro  c.mm.,  when  it  would  undoubtedly  be  too  early  to 
cease  the  treatment. 

Lenhartz,  Oppenheim,  and  Lowenstein  and  Pickert  have 
already  shown  that  the  cutaneous  reactivity  generally  dies  away 
when  a  relative  immunity  is  reached  to  the  larger  doses  sub- 
cutaneously.  Also  from  our  own  experiments,  the  cutaneous 
reaction  of  patients  specifically  treated  behaves  in  every  way 
similarly  to  the  subcutaneous,  as  would  naturally  be  expected ; 
the  cutaneous  reaction  to  old  tuberculin  disappears  earlier  than 
that  to  bacillary  emulsion,  while  patients  immunized  with  bacillary 
emulsion  no  longer  display  reaction  to  old  tuberculin. 

3_THE  SPECIFIC  REMEDIES  FOR  TUBERCULOSIS. 

In  discussing  the  various  tuberculins,  their  origin  and  mode 
of  employment,  the  three  chief  preparations  which  we  owe  to 
Koch,  will  be  taken  as  a  basis,  and  following  on  them  a  resume 
given  of  other  specifics  which  have  obtained  some  vogue.  These 
will  be  treated  in  the  detail  due  to  their  relative  importance 
and  the  place  they  have  obtained  in  therapeutics,  so  that 
the  reader  may  obtain  a  grasp  of  the  whole  subject  in  correct 
proportion. 

.    ,.  .   ,_.       .       Distinction    must    at    the    outset    be    made 

Active  and   Passive  ,  .  .... 

between  preparations  which  aim  at  pro- 
immunity,  ducing.  an  active  immunity  and  those 
designed  to  produce  a  passive  one.  Bv  active  immunization  is 
understood  the  change  in  the  organism  which  results  from  the 
absorption  of  bacteria  or  their  products,  and  which  leads  to  the 
appearance  of  specific  protective  bodies  (antibodies)  in  the  serum. 
This  form  of  immunization  is  therefore  an  indirect  one,  the 
organism  having  to  prepare  its  own  protective  bodies  and  hence  is 
called  with  Ehrlich  active  immunization.     By  passive  immuniza- 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS  I  59 

tion,  on  the  other  hand,  is  understood  the  production  of  immunity 
by  means  of  a  specific  serum.  The  organism  appropriates  protec- 
tive bodies, ready  formed  by  another  individual;  it  has  itself  no 
effort  to  exert,  the  process  being  a  passive  one. 

(a)  Preparations  Designed    to  Produce  Active 

Immunity. 

(i)  OLD  TUBERCULIN  (AT). 

The    first    tuberculin    prepared,    by    Koch, 

Preparation.         called    "old"    tuberculin    to   distinguish   it 

from  the  newer  productions,  was  prepared  in  the  following  way  :  — 

Pure  cultures  of  tubercle  bacilli  which  had  grown  four  to  six  weeks  on 
5  per  cent,  glycerine-broth  were  sterilized  with  the  culture  fluid  by  heating 
in  steam  for  one  hour  and  concentrated  at  a  reduced  temperature  to  one- 
tenth  of  the  volume.  After  the  steaming  the  liquid  was  removed  from  the 
tubercle  bacilli  by  filtering. 

Old  tuberculin   is   not  a   true   toxin   nor   is 

Nature.  jt  a  pure  endotoxin.     It  contains  essentially 

the  soluble  secretions  of  the  tubercle  bacilli  (toxins)  in  50  per  cent. 

glycerine  dilution  and  also  the  constituents  of  the  bodies  of  the 

bacilli    (endotoxins),    extracted    during    the    hour's    heating    and 

steaming  by   the   alkali   and  glycerine   contained   in    the   culture 

broth. 

^  r       In  sanatoria  with  laboratories,  sterile  eradu- 

Preparation  of  .     .  r    „  .,  ° 

ated  pipettes  of  all  sizes  are  accessible  and 

the  dilutions  may  be  made  in  various  ways. 
From  100  c.mm.  upwards,  the  dose  is  taken  with  a  sterile  syringe 
direct  from  the  original  fluid.  For  private  practice  the  following 
method  is  to  be  recommended,  the  diluting  fluid  being  \  per  cent, 
phenol  solution. 

We  preface  the  instructions  with  the 
' '  advice  :  the  physician  employing  tuberculin 

in  therapy  should  not  seek  to  avoid  the  small  amount  of  labour 
involved  in  preparing  the  dilutions  himself.  More  and  more 
workers  assert  that  there  is  often  a  great  difference  between  per- 
sonally prepared  and  bought  dilutions,  in  favour  of  the  former. 
This  is  a  question  of  weakening  by  keeping  the  ready-made  dilu- 
tions too  long  in  stock.  This  calls  for  care.  If  ready-made 
dilutions  are  bought,  these  must  bear  the  date  of  preparation. 
Therefore  we  are  anxious  that  all  dilutions  prepared  under  the 
inspection  of  the  Farbwerke  Hoechst  shall  be  labelled  with  the  date 
of  preparation,  and  only  supplied  within  a  certain  time  according  to 


l6o  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

the  concentration.  We  may  note  here  that  the  i  :  10  dilution  of 
the  original  fluid  remains  unchanged,  but  that  the  stability  of  the 
weaker  solutions  decreases  continuously  according  to  the  grade  of 
dilution. 

A    number    of    wide-necked    stoppered    bottles    of 
rTOCedure.  brown     glass     and     about     10     c.c.     capacity     are 

obtained.  These  are  first  sterilized  by  boiling.  The  contents  remain  sterile 
when  protected  from  gross  contamination,  since  the  diluting  fluid  is  |  per 
cent,  phenol.  To  ensure  continued  sterility,  the  bottles,  when  quite  or 
nearly  empty,  are  occasionally  filled  quite  up  with  the  diluting  fluid,  the 
stopper  gently  inserted  and  the  whole  inner  surface  of  the  bottle  and  stopper 
left  until  next  used  in  contact  with  the  disinfecting  fluid.  For  the  sake  of 
simplicity  the  dilutions  are  all  made  with  a  i  c.c.  syringe. 

Solution  (i)  :  5  divisions  (tenths)  of  the  syringe  from  the  original 
solution  =  500  c.mm.,  plus  4I  syringefuls  of  the  diluent.  Then  each  syringe- 
ful  contains  100  c.mm.  tuberculin  or 

10  divisions  =  100  c.mm. 
1   division     =     10      ,, 

Solution  (2)  :  s  divisions  from  No.  1  solution  =  50  c.mm.,  plus  4i 
syringefuls  of  the  diluent.  Then  each  syringeful  contains  10  c.mm.  tuber- 
culin or 

10  divisions  =  10  c.mm. 
1   division    =     1      ,, 

Solution  (3)  :  5  divisions  from  No.  2  solution  —  5  c.mm.,  plus  4.5  syringe- 
fuls of  the  diluent.      Then  each  syringeful  contains  1  c.mm.  tuberculin  or 

10  divisions  =  i'o  c.mm. 
1   division    —  o'i        ,, 

Solution  (4)  :  5  divisions  from  No.  3  solution  =  o'5  c.mm.,  plus  4i 
syringefuls  of  the  diluent.  Then  each  syringeful  contains  o'i  c.mm.  tuber- 
culin or 

10  divisions  =     o'i   c.mm. 
1   division    =  o'oi        ,, 

Solution  (5)  :  5  divisions  from  No.  4  solution  =  o'os  c.mm.,  plus  4! 
syringefuls  of  the  diluent.  Then  each  syringeful  contains  o'oi  c.mm.  tuber- 
culin or 

10  divisions  =     o'oi   c.mm. 
1   division    =  o'ooi        ,, 

N.B. — If  only  a  few  injections  are  to  be  given  and  fresh  solutions 
always  required,  3  instead  of  5  divisions  of  the  next  stronger  concentrated 
solution  may  be  taken,  plus  2  whole  syringefuls  and  7  divisions  of  the 
diluent. 

All  the  bottles  must  be  labelled  in  ink  in  order  to  prevent  mistakes, 
and  the  labels  should  be  varnished  over.  All  solutions  must  be  kept  cool 
and  in  the  dark,  best  of  all  in  a  refrigerator. 

Sterilization    of        RuPPel    D/2!    gives  an   emphatic  warning   against 

heating  the  prepared  dilutions  in  order  to  sterilize 

Dilutions.  them.    Undiluted  tuberculin  can  be  heated  for  a  long 

time  in  the  autoclave  up  to  1500  C.  without  its  specific  effect  being  injured. 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        l6l 

But  in  dilutions  the  effective  substance  is  injured  by  heating,  in  high  dilutions 
almost  entirely  destroyed.  Our  tests  have  shown  that  this  is  true  in  dilutions 
of  a  millionth  and  hundredth  thousandth  part  of  a  cubic  centimetre.  It  is, 
however,  necessary  to  heat  the  dilution  for  a  few  minutes;  mere  boiling 
up  does  not  weaken  the  effect  of  the  highest  dilutions  used. 

N.B. — A  rule  which  is  really  self-evident  but  nevertheless  often  broken, 
is  that  when  a  number  of  injections  are  to  be  made,  commencement  should 
be  made  with  the  weakest  solution,  proceeding  to  the  next  stronger.  But 
if  a  weaker  solution  has  to  be  used  after  a  stronger,  the  syringe  must  be 
cleansed  by  repeated  rinsings  with  the  diluent. 

In  favourable  cases  in  the  first  and  second 
Initial  Uose.  stadium  (Turban),  where  the  general  con- 
dition and  bodily  strength  is  good  and  the  mouth  temperature 
does  not  exceed  370  C.  during  the  day,  a  dose  of  o"i  c.mm.  may 
be  used  to  begin  with.  If  reactions  follow  even  this  dose,  or  if 
the  temperature  several  times  during  the  daytime  has  been  above 
370  C,  the  dose  should  be  reduced  to  o"oi  c.mm.  In  the  great 
majority  of  cases  of  good  prognosis,  including  those  of  the  third 
Stadium,  it  will  not  be  necessary  to  go  below  this  dose  to  start 
with ;  it  has  not  been  necessary  in  the  case  of  a  single  patient  in 
the  sanatorium.  On  the  other  hand,  Hammer  has  seen  a  severe 
general  reaction  occur  even  after  a  dose  of  o'oo2  c.mm.,  and  he 
recommends  in  such  cases,  which  are  clinically  less  favourable 
and  of  doubtful  prognosis,  to  start  with  o'ooi  c.mm. 

0  With    small    doses    up    to     10    c.mm.    an 
Sequence  of  r  r      ,.   .  . 

'  increase  or   one  or  more  divisions  may  be 

made   at   each    injection,    according   to   the 
degree  of  susceptibility  shown;  thus:  — 

0*001,  0*003,  o'oo6,  o'oi  c.mm. 
(i.e.,  Sol.  (5)  :  1,  3,  6,  10  divisions). 

0*015,  0*03,  o'o6,  o'l  c.mm. 
(i.e.,  Sol.  (4)  :   ij,  3,  6,  10  divisions). 

0*15,  o'2,  o'3,  o'5,  o'7,  i'o  c.mm. 
(i.e.,  Sol.  (3)  :  ij,  2,  3,  5,  7,  10  divisions). 

i'5i  2>  3>  5>  7>  IO  c.mm. 
(i.e.,  Sol.  (2)  :  ij,  2,  3,  5,  7,  10  divisions). 

If  slight  reactions  occur  no  increase  should  be  made,  but  the 
same  dose  repeated;  if  more  severe  reactions  occur  the  interval 
should  be  lengthened  or  a  smaller  dose  given,  as  has  already  been 
discussed  in  more  detail.  One  point  must  be  specially  empha- 
sized :  on  passing  from  *or  to  0*02  c.mm.,  from  o"i  to  0*2  c.mm., 
and  from  1  to  2  c.mm.,  the  dose  would  be  doubled.  These  are, 
as  a  rule,   the  critical   points  where  reactions  first   occur.     This 

1  T 


1 62  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

relatively  rapid  rise  is  not  of  much  importance  with  solution  4; 
but  it  frequently  produces  its  effect  in  passing  from  01  to 
o"2  c.mm.,  more  frequently  from  1  to  2  c.mm.,  and  from  10  to 
20  c.mm.  Therefore  here  it  is  advisable  to  increase  the  dose  by 
only  half  a  division,  that  is  from  o-i  to  C15  c.mm.,  from  1  to 
1*5  c.mm.,  and  from  10  to  15  c.mm.  (See  our  directions  as  to 
the  graduation  of  the  syringe.) 

If  the  rise  from  10  to  15  c.mm.  is  well  borne,  from  20  c.mm. 
upwards  an  increase  of  one  or  more  whole  divisions  at  a  time 
may  be  tried;  thus  :  — 

15,  20,  30,  50,   70,    100  c.mm. 
(i.e.,  Sol.  (1)  :  ij,  2,  3,  5,  7,  10  divisions). 

From  100  c.mm.  upwards  at  first  an  increase  of  only  half  a 
tenth  of  a  division  should  be  made ;  if  no  reaction  occurs  then 
a  rise  of  one  or  even  several  tenths  of  a  division  may  be  made ; 
thus :  — 

Original  solution  (old  tuberculin)  ij,  2J,  4,  6,  8,  10  divisions. 

If  reaction  occurs  the  procedure  already  mentioned  must  be 
returned  to.  We  have  been  induced  to  discuss  the  dosage  in 
such  minute  detail  as  we  have  repeatedly  been  referred  to  for 
advice  even  by  those  versed  in  tuberculin  treatment  who  have 
found  difficulties  in  determining  the  best  graduation  to  avoid,  as 
far  as  may  be,  any  reaction.  And  what  has  been  said  here  for 
Koch's  tuberculin  applies  also  in  principle  to  all  other  tuberculin 
preparations. 

It  is  in  general  the  practice  to  inject  each  dose  in 

Concentration  the    concentration    in    which    it    is   drawn   into    the 

Of  the    Dose  syringe.      By  many,  however,  the  injection  of  large 

.    •      ,      1  doses    (from    about    10    c.mm.    upwards)    in    small 

-*  '  quantities   of   one  or   two   divisions  is   avoided,   in 

order  not  to  excite  local  irritation;  the  injection  dose  is  made  up  to  1  c.c. 

with  normal   saline.     According  to   our  observations,  there  is  no   necessity 

for  such  a  precaution. 

'  With    regard   to    the    interval   between    the 

successive  doses,  they  may  in  general 
be  given  twice  a  week.  In  the  case  of  tenths  and  hundredths  the 
interval  may  be  reduced  to  one  day;  above  10  c.mm.  it  should  be 
not  less  than  three  clear  days ;  and  with  the  larger  doses  of 
100  c.mm.  and  more,  four  to  seven  days.  Whenever  the  period 
of  treatment  allows  we  go  on  to  1,000  c.mm. 

Chart  13  is  a  specimen  of  a  course  of  tuberculin  entirely  •  without 
reaction. 

Chart  14  is  an  example  of  a  second  shorter  course  in  the  same  patient 
six  months  after  completion  of  the  first. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  163 

Chart  15  illustrates  the  method  of  small  reactions,  avoiding  any  con- 
siderable rise  of  temperature. 

Chart  16  illustrates  the  fact  that  moderate  reactions  are  not  always  to 
he  avoided  even  with  careful  dosage  and  shows  the  procedure  when  such 
reactions  occur  (repetition  of  the  same  dose,  increase  of  the  interval). 

The  maximal  dose  may  be  repeated  several 
Maximal  Dose.  times  at  increasing  intervals;  its  repetition 
depending,  apart  from  the  patient's  circumstances,  on  the  physical 
signs.  All  that  has  yet  been  said  applies  only  to  cases  which 
take  a  smooth  and  normal  course.  The  general  principles  stated 
earlier  will  determine  the  absolute  and  the  individual  maximal 
dose  and  the  procedure  in  case  of  reaction  occurring. 

n  .   .      .  In  connection  with  Denys'  tuberculin,  which 

.  will  be  considered  later,   it  must  be  noted 

Tuberculin.  that     loch's     animal     experiments     were 

carried  out  with  tuberculin  which  had  not  been  concentrated  to 
one-tenth  of  its  volume  and  to  which  he  gave  the  name  "  original  " 
tuberculin  (TO);  but  these  were  not  published.  In  1893,  Koch 
handed  over  this  original  tuberculin  to  Carl  Spengler  for  further 
study  in  animals  and  human  beings,  and  until  Denys'  publica- 
tions Spengler  alone  made  any  communications  with  reference  to 
original  tuberculin.  As  definite  good  results  have  been  obtained 
with  the  non-concentrated  broth  culture  and  since  the  preparation 
has  been  extensively  used,  especially  in  Belgium  and  Switzerland 
owing  to  its  low  toxicity,  the  firm  Farbwerke  Hoechst  has  met 
the  demand  for  this  original  tuberculin  and  supplies  it  under  the 
letter  TOA  (Tuberculin-Original-Alt). 

This  consists  of  a  filtered  culture  of  tubercle  bacilli  of  human 
origin,  not  concentrated  by  boiling  and  completely  free  from  the 
rjacillary  bodies  themselves.  It  contains  exclusively  substances 
which  have  been  produced  by  the  tubercle  bacilli  during  their 
culture,  and  abstracted  by  the  culture  fluid  (toxins),  whilst  old 
tuberculin  contains,  besides  these  toxins,  substances  which  are 
extracted  from  the  bodies  of  the  tubercle  bacilli  at  a  higher 
temperature  (endotoxins).  As  it  is  not  exposed  to  heat  for  an 
hour  it  is  believed  in  many  quarters  that  it  contains  the  specific 
substances  of  tuberculin  in  an  unchanged  state. 

1    c.c.    of   TOA  corresponds  to  the    10th  part  or  o'i    c.c.    of  old  tuber- 
culin. 

With  this  preparation  we  have  treated  about  sixty  cases  in 
all  stages.  It  is  distinguished  from  old  tuberculin  by  its  lower 
toxic  power,  due,  on  the  one  hand,  to  its  being  ten  times  weaker ; 
.and,  on  the  other  hand,  to  the  absence  of  the  substances  extracted 


164  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

from  the  bodies  of  the  tubercle  bacilli.  Patients  who  are  immune 
to  original  tuberculin,  sometimes  react  even  severely  to  50  c.mm. 
of  old  tuberculin.  We  have  not  noticed  any  superiority  in  its 
therapeutic    efficacy    to    the    concentrated    tuberculin    (cf.    Chart 

17)- 

w  The    Farbwerke    Hoechst    also    prepare    a 

form     of     TOA,     concentrated     at     a     low 
Tuberculin.  temperature     under     reduced     pressure     to 

1/10  of  its  volume,  the  Vacuum  Tuberculin  of  Carl  Spengler. 
Vacuum  tuberculin  is  quantitatively  identical  in  action  with 
TOA,  its  advantage  lying  only  in  the  fact  that  it  will  keep 
better  and  longer. 

1  c.c.  vacuum  tuberculin  =  10  c.c.  TOA  =  1  c.c.  old  tuberculin. 
X.B. — These  three  preparations  are  also  manufactured  in  a  similar  way 
from  cultures  of  the  tubercle  bacilli  of  the  bovine  type. 

_  _,  ,  At   the   instigation    of   R.    Koch,    we   have 

Bovine  Old  .  .       .         ,,       ,         ,.  ,         . 

used  bovine  old  tuberculin  prepared  at  the 

u      re     in.  Koch  Institute  on  a  large  number  of  cases, 

curable  or  capable  of  improvement.  Excellent  results  have  fol- 
lowed its  use,  but  in  a  material  of  nearly  300  cases  of  all  stadia 
we  have  not  been  convinced  that  its  curative  effect  is  greater 
than  that  of  tuberculin  of  human  origin.  Bovine  old  tuberculin 
doubtless  -possesses  very  considerably  fewer  toxic  properties  and 
has  a  milder  action  than  the  human  tuberculin  of  analogous 
preparation  (cf.  Chart  18).  It  is  as  well  borne  as  the  above 
described  original  tuberculin  (TOA).  The  non-concentrated 
bovine  preparation — bovine  original  tuberculin — which  we  have 
also  used,  has  a  still  milder  action ;  this  does  not  contain  the 
extractive  substances  from  the  bacillary  bodies. 

(2)  ALBUMOSE-FREE  TUBERCULIN  (AF). 

Koch,    shortly  before  his  death,   instituted 
History.  experiments      in      the      Rudolf      Virchow 

Hospital  with  tuberculin  grown  on  media  free  from  albumose. 
This  preparation  was  introduced  as  an  attempt  to  avoid  the  fever 
caused  by  albumoses,  for  in  susceptible  patients  anaphylaxis  may 
be  produced  by  the  repeated  injection  of  tuberculins  rich  in  the 
latter.  Albumose-free  tuberculin  is  now  prepared  by  the  Hoechst 
Farbwerke  in  the  following  manner  :  — 

Mode    of  Erlenmeyer  flasks  are  filled  with  an  albumose-free 

culture     fluid      (Koclr's      prescription  :      Potassium 
Preparation.  phosphate,  ■  0*5  ;    magnesium    sulphate,    o'o6;    mag- 

nesium  citrate.   0*25;   asparagin,  0*5 :    glycerine,   2*0;    soda,    0*25 ;    distilled 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  165 

water,  100  parts),  inoculated  with  a  pure  culture  of  human  tubercle  bacilli 
and  left  in  the  incubator  at  37°  C.  until  the  surface  of  the  culture-fluid  is 
covered  with  a  thick  growth  of  pure  culture  and  the  volume  is  reduced  to  tu 
of  the  original  quantity.  As  soon  as  this  has  occurred,  the  bacilli  are  killed 
by  heating  for  two  hours  at  6o°  C.  on  two  successive  days  and  separated 
by  continued  filtration  from  the  culture  fluid.  The  latter,  after  the  addition 
of  o"5  per  cent,  phenol  for  a  sufficient  length  of  time  to  kill  any  bacilli 
which  may  still  be  present,  constitutes  albumose-free  tuberculin  ready  for 
use.     It  corresponds  in  all  particulars  to  Koch's  old  tuberculin. 

For  two  years  we  have  made  extensive  tests 
Properties.  with.  t^-ls  new  preparation  and  have  treated 

several  hundred  cases  with  it.  Our  opinion  as  to  its  activity  is 
that  it  is  better  tolerated  than  old  tuberculin,  even  by  very 
sensitive  patients ;  that  in  the  latter  the  treatment  can  be  carried 
out  to  the  end  without  trouble,  while  with  the  smallest  doses  of 
old  tuberculin  slight  febrile  reactions  and  disturbances  of  the 
general  condition  impede  progress.  Needle-track  reactions  are 
considerably  slighter,  infiltrations  practically  never  occur.  The 
absence  of  these  general  and  local  symptoms  is  probably  due  to 
the  exclusion  of  albumoses  and  certain  toxic  substances  which 
arise  in  the  concentration  of  the  preparation  at  high  temperatures. 
The  action  of  albumose-free  tuberculin  is  not  inferior  to  old 
tuberculin  ;  but  the  larger,  more  active  doses  of  the  former  are 
more  easily  and  quickly  reached,  and  as  a  successful  tuberculin 
cure,  at  any  rate  in  open  pulmonary  tuberculosis,  cannot  be  made 
without  the  large  doses,  this  is  an  advantage.  The  special  merit 
of  albumose-free  tuberculin  seems  to  us  to  be  that,  owing  to  the 
absence  of  certain  toxic  properties  present  in  old  tuberculin,  it  is 
particularlv  suitable  for  ambulant  treatment,  which  will  be  the 
more  easily  carried  out  to  the  large  extent  we  desire  the  better 
the  tuberculin  is  tolerated  and  the  less  the  reactions  it  causes. 
We  have  not  observed  an  antipyretic  action  to  any  great  extent ; 
at  any  rate,  in  this  respect  albumose-free  tuberculin  is  much 
inferior  to  bacillary  emulsion  ;  but  the  latter,  in  its  character  as 
an  emulsion,  is  more  likely  to  cause  difficulties  in  ambulant 
practice. 

In    some    quarters    complaints    have    been 
CTivity.  made     that     albumose-free     tuberculin      is 

irregular  in  action  and  causes  uncalled-for  high  febrile  reactions. 
The  explanation  of  these  phenomena  does  not  lie  in  any  imper- 
fection in  the  preparation  itself,  but  in  the  insufficient  knowledge 
of  the  constancy  of  its  action.  The  original  concentration  to  a 
quarter  of  the  volume  was  given  up  owTing  to  the  poor  durability 
of  the  preparation.  Further  experiments  have  taught  that  even 
in  a  concentration  of  one-tenth  of  the  original  volume  a  certain 


1 66  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

instability  is  present  during  the  first  three  months,  sometimes  one 
way,  sometimes  the  other.  After  this  it  remains  absolutely  un- 
changed. Now  this  preparation  is  not  only  tested  for  toxicity 
under  Government  control  on  animals  like  old  tuberculin,  but 
its  activity  is  also  more  exactly  determined  by  the  agglutination 
and  complement-binding  tests.  The  Hoechst  Farbwerke  further 
take  great  care  that  only  constant  preparations  are  put  on  the 
market. 

^  The    dosage    of    albumose-free    tuberculin 

Dosasre. 

7  should    follow    the    same    lines    as    for    old 

tuberculin.  Chart  19  is  an  example  of  a  completely  reactionless 
course  with  a  fairly  rapid  rise  of  dose.  Chart  20  shows  an 
equally  favourable  course  with  some  slight  febrile  temperatures,, 
the  dose  almost  always  being  increased  in  spite  of  slight, 
negligible  reactions.     Loss  of  fever  occurred. 

The  experiences  of  Jochmann  and  Mollers 
Experiences  with     [173]    in    about    150    cases    of    pulmonary 
Albumose-free       tuberculosis  of  the  first  and  second  stadia 
Tuberculin.  with    regard    to    the    susceptibility    to    old 

tuberculin  of  patients  treated  with  albumose- 
free  tuberculin  are  worthy  of  note.  They  found,  and  we  can 
completely  confirm  their  observations,  that  this  susceptibility  is 
but  little  diminished  by  the  previous  treatment,  presumably  be- 
cause old  tuberculin  possesses  toxic  substances  extracted  by  heat 
which  are  not  contained  in  albumose-free  tuberculin.  Patients 
immunized  to  1  c.c.  of  albumose-free  tuberculin  react  with  high 
fever  even  to  a  twentieth  part  of  old  tuberculin.  This  is  of 
importance  in  practice  inasmuch  as  it  is  not  advisable  to  follow 
up  a  course  of  albumose-free  tuberculin  with  one  of  old  tuberculin. 
On  the  other  hand,  after-treatment  with  bacillary  emulsion  is  well 
borne  and  can  be  completed  relatively  quickly,  since  the  sensitive- 
ness to  bacillary  emulsion  is  diminished  by  previous  treatment 
with  albumose-free  tuberculin,  just  as  with  old  tuberculin. 

At  the  Congress  of  Tuberculosis  in  191 1,  albumose-free  tuberculin 
was  awarded  an  extremely  favourable  judgment,  corresponding  on  tha 
whole  with  our  experience  cited  above.  Beninde,  Holdheim,  Meyer  and 
Sobotta  all  expressed  their  satisfaction  with  the  preparation.  Ziegler  even 
stated  that  he  obtained  far  better  results  than  with  any  other  preparation ; 
he  described  it  as  mild  and  efficacious,  specially  valuable  in  reducing  feve.. 
and  gradually  decreasing  and  finally  eliminating  tubercle  bacilli  from  the 
sputum.  He  recommends  it  without  reservation  as  the  specific  tuberculin 
in  pure  form,  free  from  foreign  albumin  and  organic  extractives.  Brecke 
emphasizes  the  absence  of  any  unpleasant  phenomenon  following  the  injec- 
tions, but,  with  us,  holds  that  it  is  not  yet  proved  more  efficacious  than  the 
other  preparations  of  Koch,  especially  bacillary  emulsion.     Landmann  holds 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  l6/ 

that  the  one  and  only  advantage  of  the  preparation  is  that  it  is  not  heated 
during  its  manufacture. 

Further  confirmation  on  the  above  lines  has  been  afforded  by  Freymuth, 
Orszag,  and  Spitzstein. 

(3)    NEW   TUBERCULIN    (TR). 

For  his  later  preparations  of  tuberculin,  Koch  [174]  adopted 
a  new  method. 

With  old  tuberculin  the  aim  is  the  attainment  of 

TOXIC  immunity    simply   against    the    bacterial    toxin;    on 

and    Bacterial  the    bacilli    themselves    the    immunity   has    no    in- 

,  ..  fluence.     The  conditions  are  similar  to  the  case  of 

Immunity.  ,     ,u         ,        tl  a  ., 

1  tetanus  ;  the  filtrate  from  the  culture  fluid  contains 

the  soluble  products  of  the  tetanus  bacilli  with  their  specific  toxins ;  against 
this  toxin  the  immunized  animals  are  protected,  but  the  bacteria  themselves 
are  unharmed,  they  continue  to  live  and  may  eventually  kill  the  animal 
after  the  tox-immunity  has  passed  off.  On  the  other  hand,  with  cholera 
and  typhoid  it  is  a  question  of  a  pure  bacterial  immunity ;  the  animals  treated 
with  fresh  agar  cultures  are  protected  against  the  bacteria  but  not  against 
the  toxins  secreted  by  them.  Living  bacteria  are  soon  destroyed  in  the 
body  of  the  immunized  animal,  although  no  one  has  yet  been  successful  in 
immunizing  the  animals  beyond  a  certain  limited  dose  of  toxin.  Koch's 
aim  was  to  combine  both  these  forms  of  immunity  in  his  treatment  of  tuber- 
culosis. He  thought  he  recognized  a  tendency  towards  immunity  in  the 
miliary  tuberculosis  of  man  and  the  experimental  tuberculosis  of  the  guinea- 
pig.  A  stage  occurs  in  which  it  is  extremely  difficult  to  find  any  trace  of 
the  bacilli  which  were  at  first  present  in  great  numbers.  It  appears  here  to 
be  a  question  of  a  real  process  of  immunization  against  the  bacteria,  but 
one  which  is  already  too  late.  Koch  aimed  at  obtaining  this  immunity  at 
an  earlier  stage  of  the  infection.  The  one  thing  necessary  was  to  flood  the 
organism  with  tubercle  bacilli.  Koch  held  that  immunity  usually  did  not 
take  place  because  the  tubercle  bacilli  are  present  in  the  tissues  in  such 
small  numbers  and  grow  so  slowly.  Where  they  multiply  actively,  e.g.,  in 
lung  cavities,  they  are  thrown  off  unchanged  and  not  absorbed  at  all.  The 
process  of  immunization,  therefore,  did  not  occur.  It  only  takes  place  when 
numerous  bacilli  distribute  themselves  rapidly  in  the  whole  body,  as  occurs 
in  fact  in  miliary  tuberculosis  and  the  experimental  tuberculosis  of  guinea- 
pigs. 

.  Koch's  aim,  therefore,  was  to  ensure  the  absorption 

^reparation    OT       Qf  as  many  unaltered  tubercle  bacilli   as  possible, 

a   Tuberculin    Con-    whether    living  or    dead.      The    attempt    failed    be- 
taining  all  the  essen-  cause  the  unaltered  bacilli  were  not  absorbed  from 

tial    Substances   of  t*le   subcutaneous  tissue,   the  peritoneal  cavity,   nor 
thf    Bacilli  from  the  circulation,  but  gave  rise  to  suppuration. 

He  then  made  the  attempt  to  obtain  by  chemical 
means,  in  a  form  which  would  be  absorbed,  all  the  substances  contained  in  the 
tubercle  bacillus  as  far  as  this  was  possible.  By  extraction  with  decinormal 
soda  the  preparation  TA  was  obtained.  This  gave  tolerable  results,  but  it 
also  contained  some  bacilli,  which,  although  certainly  dead,  gave  rise  to 
abscesses.  Finally,  Koch  obtained  a  complete  breaking-up  of  the  bacilli 
by  grinding  a  well-dried  culture   without  any  addition   in   an   agate  mortar. 


1 68  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

The  powdered  mass  was  then  stirred  up  in  normal  salt  solution  and 
separated  by  centrifugalizing  into  two  layers:  an  upper  one  TO,  very 
similar  to  TA,  and  containing  the  glycerine-soluble  substances ;  and  a  lower 
layer  TR  containing  chiefly  the  substances  left  behind  after  extraction  with 
glycerine. 

_  .  TR    unquestionably  possesses   immunizing 

P  properties,      as      Koch      demonstrated      on 

animals  and  man.  Considering  reactions 
necessary  in  the  case  of  old  tuberculin  in  order  to  obtain  any 
curative  result,  with  TR  he  sought  as  far  as  possible  to  avoid 
them.  The  immunity  is  quite  independent  of  reactions.  The 
important  point  is,  by  gradually  increasing  the  dose,  to  make 
the  individual  insensitive  to  TR,  and,  since  this  contains  all 
the  immunizing  substances  of  a  tubercle  culture,  at  the  same 
time  insensitive  to  the  tubercle  bacillus.  A  patient  immunized 
against  TR,  even  in  the  practical  absence  of  reactions,  does  not 
react  to  large  doses  of  old  tuberculin  and  is  therefore  immunized 
against  all  constituents  of  the  tubercle  bacillus. 

In  the  process  of  immunizing  healthy  animals  and  treating  infected 
ones  it  is  entirely  a  question  of  assimilating  the  largest  possible  doses. 
Koch  succeeded  in  this  way  in  completely  immunizing  guinea-pigs,  so  that 
they  stood  repeated  injections  of  virulent  cultures  without  becoming  infected. 
Even  in  the  case  of  guinea-pigs  which  were  in  too  advanced  a  stage  of  the 
disease  for  complete  recovery,  some  grade  of  retrogressive  changes  could  be 
demonstrated  after  treatment  with  TR. 

.     ,.     ..  In    advanced   cases   of    phthisis,    especially 

Indications  .  .  .  .      .*.    ,      .  '       ■,,.   ; 

those  with  severe  mixed  infection  and  high 

and  fever,   TR   should  not  be  employed.     But 

Contra-indications.  in   all   other  cases  which   Koch  treateci  he 

obtained,  without  exception,  striking  improvement,  far  exceeding 
that  with  the  old  tuberculin ;  and  among  these  were  cases  of 
lupus  where  ocular  demonstration  proved  the  healing  process 
beyond  dispute. 

The  original  solution  of  TR  contains  20  per  cent,  glycerine, 
which  acts  as  a  sufficient  preservative.  In  practice  the  dilutions 
should  be  prepared  in  the  manner  already  described;  not  with 
phenol,  but  with  physiological  saline  or  20  per  cent,  glycerine; 
the  latter  lasts  about  a  fortnight.  It  must  not  be  forgotten  in 
preparing  the  dilutions  that  TR  is  very  like  an  emulsion  and 
that  therefore  the  bottle  must  be  thoroughly  shaken  before  remov- 
ing the  tuberculin. 

, '     ".  ",  _  Koch's      instruction      is      to     begin      with 

Initial   Dose.  „.-  _  ,,        ,         4,    4  :t  . 

o  2  c.mm.,  so  small  a  dose  that  it  is  quite 

exceptional  for  a  reaction  to  occur.      If  it  does,  a  tenfold  more 

dilute  solution  is  prepared. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  1 69 

The  dose  is  to  be  so  slowly  increased  that  elevation  of  tem- 
perature by  more  than  half  a  degree  is  avoided.  Febrile  reaction 
must  have  completely  passed  off  before  the  same  dose  is  injected 
again. 

«  ..         To  avoid  repetition   the   reader  is   referred 

Sequence  of        .      ,  .     r  ,. 

^  back   to   the   very   minute   directions   given 

Doses.  jn   t^e  cage   0£  0j^   tuberculin.     Chart   21, 

that  of  a  patient  with  severe  tuberculosis  of  the  larynx  combined 
with  slight  pulmonary  disease  and  facial  lupus,  shows  how 
rapidly  the  dose  may  be  raised.  But  in  principle  the  dose  should 
be  increased  more  slowly,  since  the  rapid  rise  has  no  therapeutic 
advantage  and  may  affect  the  general  health  to  its  detriment.  On 
the  other  hand,  TR  does  not  require  anything  like  the  same 
precaution  in  its  administration  as  old  tuberculin  ;  it  is  the  mildest 
of  Koch's  preparations. 

The    intervals    are    the    same    as    with    old 

Interval.  tuberculin  :    at  first  every  other  day,   from 

about   50   c.mm.    upwards   tw7ice    in    the   week,    above    500   once 

weekly,   and  with  the  largest  doses  we  have  been   in   the  habit 

of  allowing  still  longer  intervals. 

The  maximal  dose  is  2,000  c.mm.,  which 
maximal  uose.  we  generauv  repeat  at  increasing  intervals 
of  two,  four,  six,  and  eight  weeks.  Repetition  of  the  maximal 
dose  is  always  to  be  recommended,  the  interval  varying  from 
case  to  case.  The  low  toxicity  of  TR  makes  it  very  suitable 
in  all  cases  of  great  susceptibility  to  tuberculin.  Hence  it  may 
be  used  in  such  cases,  as  Goetsch  has  advised,  as  a  preliminary 
to  a  course  of  old  tuberculin  or  of  the  bacillary  emulsion. 

We  have  recorded  a  considerable  number  of  good  results 
with  this  preparation  [162].  One  of  the  most  noteworthy  has 
already  been  alluded  to.  The  patient  was  cured  and  has  remained 
so  for  six  years.  The  liability  to  deteriorate  and  the  very  high 
cost  militate  against  its  wider  adoption. 

(4)  NEW  TUBERCULIN   BACILLARY   EMULSION   (BE). 

After  his  agglutination  experiments,  Koch  [39]  modified  his 

new  tuberculin  to  the  extent  of  no  longer  separating  TO  and 

TR.     Instead  of  centrifugalizing,   the  comminuted  bacilli,   after 

being  suspended  in  normal  saline,  were  merely  allowed  to  settle 

and  50  per  cent,  glycerine  added  for  greater  permanence. 

„     ,,     A      .    ;.  Koch's  experiments  led  to  the  result  that  it 

Koch  s  Agglutina-  ,  l  .  .      ■.,,.■.  ., 

_  .  was  better  to  emplov  the  ground-up  bacil- 

tion   Experiments.    1  -,u     *.  "  ';•  1 

^  lary    mass    without    separating    into    layers 


170  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

and  that  high  agglutination  values  were  reached  with  the  greatest 

certainty  and  speed   when   the   dose   was   rapidly   increased  and 

severe  reactions  occurred.     For- these  experiments  Koch  had  at 

his  disposal  only  very  unfavourable  material,  which  was  scarcely 

eligible  for  sanatorium  treatment.     Hence  his  results,   of  which 

he  gives  a  summary  himself,  speak  all  the  more  forcibly  in  favour 

of  specific  treatment  with  bacillary  emulsion. 

__,       «„.,,..,      ,    Our   own    researches    [40!    soon    led   us   to 
The  Mild  Method  .  ,    iU  ..  ■  1     *  .;„  „ 

avoid    the    mostly    very    violent    reactions 

°'  associated  with   Koch's  method  of  rapidly 

Administration.  increased  dosage — reactions  attended  with 
much  general  disturbance — after  the  proof  had  been  given  that, 
even  in  their  absence,  high  agglutination  values  could  be 
obtained.  This  mild  method  of  injection,  borne  very  well  by 
patients,  not  onlv  met  with  Koch's  complete  approval  but  is 
now  used  by  his  pupils  with  the  best  results  (Jochmann). 

Bacillarv     emulsion     is    a    suspension      of 
Preparation  ot       Qne     ^     of     pulverized     tubercle     bacilli 
Dilutions.  jn    IOO   parts    0f    distilled    water,    to    which 

equal  parts  of  glycerine  are  added;  by  this  addition  con- 
siderable stability  is  attained.  The  stock  solution  contains  in 
1  c.c.  5  mg.  of  solid  substance.*  From  100  c.mm.  upwards  the 
dose  for  injection  is  taken  direct  from  the  stock  solution.  In 
practice  the  following  method  of  dilution  is  recommended,  the 
diluent  being  normal  salt  solution  plus  J  per  cent,  phenol  if 
the  solutions  are  to  be  kept  several  days. 

(With  regard  to  the  size  of  the  bottles,  sterilizing,  labelling  and  storing 
them,  the  same  applies  as  for  old  tuberculin.) 

Solution  (1)  :  5  divisions  from  the  stock  solution  =  500  c.mm.,  plus  4I 
svringefuls  normal  saline.      Then  each  syringeful  contains   100  c.mm.,   or 

10  divisions  =  100  c.mm. 
1    division    =     10       ,, 

Solution  (2)  :  5  divisions  of  No.  1  solution  =  50  c.mm.,  plus  4?  syringe- 
fuls  saline.      Then  each  syringeful  contains   10  c.mm.,  or 

10  divisions  =  10  c.mm. 
1   division    =     1       ,, 

Solution  (3)  :  5  divisions  of  No.  2  solution  =  5.  c.mm.,  plus  4i  syringe- 
fuls  saline.      Then  each  syringeful  contains  1   c.mm.,  or 

10  divisions  =  i'o  c.mm. 
1   division     =  o'i        ,, 

*  As  for  TR,  the  statement  of  dosage  by  solid  substance  is  unnecessary 
and  the  doses  are  reckoned  as  before  in  cubic  millimetres.  In  the  future  the 
Farbwerke  Hoechst  will  adopt  this  method  in  their  instructions  accompany- 
ing the  tuberculin. 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        171 

Solution  (4)  :  5  divisions  of  No.  3  solution  =  o'5  c.mm.,  plus  4i  syringe- 
fuls  saline.     Then  each  syringeful  contains  o'i   c.mm.,  or 

10  divisions  =    o'i   c.mm. 
1   division    =  o'oi        ,, 

N.B. — As  we  have  to  deal  here  with  an  emulsion  the  bottle  must  be 
well  shaken  for  some  time  both  when  making  the  dilutions  and  each  time 
before  us.  Special  care  must  be  taken  with  the  original  bottle  of  tuberculin 
containing  only  1  c.c.  to  see  that  the  sediment,  which,  when  it  has  been 
standing  for  some  time,  is  somewhat  adhesive  and  cannot  be  very  clearly 
seen  through  the  brown  glass,  is  thoroughly  shaken  up. 

In  favourable  cases  of  Stadium  I  or  II  with 

good    general    health,    an    initial    dose    of 

o'i  c.mm.  may  be  given.     If  reactions  occur,   if  the  temperature 

of   the   patient  easily   rises   or   in   cases   of   doubtful    issue,    then 

begin  with  o'oi   c.mm.     One  is  very  rarely  obliged  to  go  back 

to  o'ooi  c.mm.  or  less. 

According  to  Koch's  original  instructions,  given  under  the 

influence   of   agglutination   determinations,    the    dose   should   be 

rapidly  increased  until   well-marked  reactions  occur.     Then   the 

agglutinating  power  should  be  determined  from  time  to  time  and 

be  raised  to  its  maximum  by  constantly  larger  doses  at  greater 

intervals.      Since    we    have    shown    that    immunity,     frequently 

accompanied  by  extraordinarily  high  agglutinating  values,   may 

constantly  be  obtained  by  the  milder  method,  avoiding  reaction 

altogether,  the  chief  argument  for  the  marked  reactions  falls  to 

the  ground. 

0  r         Chart  22  shows  a  case  of  open  tuberculosis 

Sequence  of  e     .  ,    _     ,.  .,..,,., 

_  oi    the    second    Stadium    with    fairly    high 

Doses.  1   .-     ,.■  j.   •  ,       r 

agglutinating  power.     It  is  an  example  of 

the  method  of  treatment  with  slight  reactions  and  rapid  rise  of 

dose.     A  course  entirely  without  reactions  may  also  be  achieved 

by  following  the  directions  given   under  Old  Tuberculin  ;   it   is, 

however,   more  difficult,  and  greater  care  must  be  taken   in  the 

observation  of  all  the  principles  laid  down  in  the  general  section. 

The  dosage  may  be  somewhat  as  follows  :  — 

0*01,  0*03,  o"o6  c.mm. 
(i.e.,  Solution  (4)  :  1,  3,  6  divisions). 

o"i,  o"2,  o\3,  0*5,  o'7  c.mm.  With   one   to 

(i.e.,  Solution  (3)  :  1,  2,  3,  5,  7  divisions).       V         two  days' 

x>  i'5>  2>  3,  5»  7  c.mm;  interval. 

(i.e.,    Solution    (2):     1,    ij,    2,3/5,    7>    divi- 
sions). ' 


172  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

1      With  two  to 
10,   15,  20,  30,  50,  70  c.mm.  ^^ 

(i.e.,  Solution  (1)  :    1,   if,  2,^3,  5,  J  divisions).   (  interval. 

Stock  Solution  (B.E.)  :  100,  150,  200,  300,  400,  \         w_th  three 

=;oo,  600  c.mm.  '  ,       , 

r      ...  c.     ,     c   1    .!  i  >  '■       to  four  days 

(i.e.,    Stock   Solution  :    1,    if,    2,    3,    4,    5,    6 

divisions). 

Stock    Solution     (B.E.)  :     800,    1,000,    1,200, 

1,400,   1,600,   1,800,  2,000  c.mm. 


interval. 


With  four,  six, 


/•         c:     i'c'i   *•'  o'     '  '  c      o    1       and  ten  days' 

(i.e.,   Stock  Solution  :    8,    10,    12,  14,    16,    18,  .  J 

d.  .       .  1  interval, 

lvisions). 

With  susceptible  patients,  only  increase  the  dose  by  100  c.mm. 

at  a  time  for  the  larger  doses  in  order  to  avoid  severe  reactions. 

It_  is  also  advisable  in  such  cases  to  lengthen  the  intervals,   by 

which  means  the  occurrence  of  reactions  is  more  easily  avoided. 

The  noticeably  slight  increase  in   temperature  with   large  doses 

in  Chart  22  may  be  looked  upon  as  immunity  reactions;  this  is 

shown  by  the  fact  that  in  spite  of  increase  of  dose  they  become 

steadily  lower.     We  consider  2,000  c.mm.  as  the  maximum  dose; 

larger  doses  are  often  not  fully  absorbed.     The  maximum  dose 

may    be    repeated    several    times    with    pauses    of    from    ten    to 

fourteen   days;  the  principles  explained  before  hold  good  here. 

A    ..  ..  The    aniipvretic    action    of    T.R.    and,    in 

Antipyretic 

;  higher  degree,  of  the  bacillary  emulsion  has 

been  emphasized  on  various  sides.  Krause 
[175]  especially  speaks  well  of  the  bacillary  emulsion  in  this 
respect.  He  was  able,  with  very  careful  dosage,  to  abolish  fever 
permanently  in  all  cases,  even  in  country  practice,  under  the  most 
unhygienic  surroundings  imaginable ;  in  some  cases  fever  dis- 
appeared which  had  withstood  all  other  methods  of  treatment 
for  a  year. 

Our  own  experiences,  too,  are  ever  more  favourable  the  longer 
we  use  the  preparation.  The  abolition  of  fever  often  succeeds 
without  noticeable  reactions  with  the  use  of  small  increasing 
doses ;  it  is  only  seldom  that  we  are  obliged  to  produce  consider- 
able reactions  at  intervals  of  from  eight  to  ten  days.  For  this 
method  the  destructive  processes  in  'the  lung  must  not  be  too 
advanced,    nor  must   severe   mixed   infection   be   present. 

Chart  23  illustrates  the  rapid  cessation  of  fever  in  a  severe 
case  of  subacute  caseous  phthisis  in  which  there  had  been  high 
to  moderate  fever  for  four  months.  The  antipyretic  action  is 
obvious  even  from  the  first  doses,  which  were  always  raised  by 
about  one  half  without  the  frequent  occurrence  of  the  more  severe 
reactions. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  1 73 

Chart  24  shows  a  more  gradual  cessation  of  fever  in  a  chronic 
caseo-fibrous  case  with  slight  febrile  symptoms.  Here,  too,  the 
loss  of  fever  was  secured  with  continuous  rise  of  dose  without 
perceptible  reactions.  Only  after  complete  loss  of  fever  did  a 
severe  reaction  occur  when  a  rather  large  dose  was  given  ;  the 
chart  shows  the  method  of  procedure  and  how  after  a  fairly  long 
pause  the  same  dose  may  be  gradually  tolerated. 

Bovine  bacillary  emulsion  is  analogous  to 
..'""     '  the  bacillary  emulsion  from  human  bacilli, 

.  Bacillary  j3Ut    prepared    with     the    bovine    type    of 

Emulsion.  bacillus.     Between  the  two  preparations  we 

have  not  been  able  to  recognize  any  difference  in  therapeutic 
activity  nor  any  distinct  difference  in  toxicity.  This  was  very 
obvious  from  the  mere  fact  that  the  bacillary  emulsion  from 
Koch's  Institute,  which  we  used  for  a  long  time,  was  sometimes 
prepared  from  human  strains  and  sometimes  from  bovine  without 
any  characteristic  differences  being  noticed  in  their  use.  Koch's 
own  experiments  had  proved  a  difference  of  species  between  the 
living  bacteria  but  not  of  their  metabolic  products  and  cell- 
substances;  further,  the  preparation  of  bacillary  emulsion  in 
Koch's  Institute  was  preferably  performed  with  bovine  bacilli 
owing  to  their  conception  of  the  harmlessness  of  working  with 
the  bacillary  particles  for  the  laboratory  assistants.  As  a  matter 
of  fact,  the  use  and  action  of  bovine  bacillary  emulsion  was  thus 
both  known  to  and  practised  by  us  before  the  publications  of 
Carl  Spengier,  which  we  shall  describe  later. 

(5)    SENSITIZED    BACILLARY    EMULSION    (SBE). 

At     the     suggestion     of     F.     Meyer,    the 
Hoechster    Farbwerke    have   made   a   sensi- 
Bacillary  dzed      baciliary      emulsion      (SBE),       the 

Emulsion  (SBE).  Hoechst  "  Tuberkulose-Sero-Vakzin."  The 
production  of  sensitized  tubercle  bacilli,  i.e.,  tubercle  bacilli 
rendered  capable  of  fixation  of  complement,  rests  on  the  Behring 
principle  of  the  weakening  of  an  antigen  by  the  addition  of  serum, 
which  he  first  applied  in  the  immunization  of  the  guinea-pig  to 
tetanus  toxin.  It  is  prepared  with  a  tubercular  serum  of  high 
value,  which  by  its  specific  amboceptor  (antituberculin)  content 
is  intended  to  destroy  the  toxic  effect  of  the  tubercle  bacilli.  The 
Hoechst  tubercular  serum  contains,  besides  the  antituberculin, 
agglutinins,  precipitins,  and  bacteriotropins.  By  the  action  of 
the  serum  on  whole  and  ground  tubercle  bacilli,  the  antibodies 
contained  in  it  are  anchored  by  the  respective  receptors  of  the 
bacilli.  ;  Insoluble  compounds  of  bacillary  substance  and  specific 


174  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

antibodies  are  formed  which  are  absolutely  non-toxic  to  healthy 
and  tubercular  individuals  and  affect  tubercular  processes  in 
guinea-pigs  in  a  striking  manner. 

Mode  of  This    emulsion    is    made    by    the    Hoechst 

Preparation.  Farbwerke  in  the  following  way  :  — 

Well-washed  and  dried  tubercle  bacilli  of  the  typus  humanus  are  mixed 
with  a  quantity  of  the  fresh  tubercular  serum,  varying  according  to  the 
amount  of  the  specific  antibodies.  This  mixture  is  left  several  days  in  the 
incubator  at  27°  C.  and  is  then  placed  in  a  shaking  apparatus  with  glass 
beads  and  shaken  until  in  a  sample  tested  no  whole  tubercle  bacilli  can  be 
found.  Then  the  crushed  bacilli  are  separated  centrifugally  from  the  serum, 
washed  with  normal  saline  and  finally  worked  up  into  a  fine  emulsion  with 
40  per  cent,  glycerine  water,  to  which  o's  per  cent,  of  carbolic  acid  is  added. 
The  content  of  bacillary  matter  amounts  as  in  the  usual  bacillary  emulsion 
to  5  mg.  in   1   c.c. 

The  Hoechst  Farbwerke  supply  the  emulsion  in  the  original  concen- 
tration and  in  6  dilutions  ready  for  use  in  descending  powers  of  10,  from 
1  :  10  to  1  : 1,000,000,  made  with  o'5  per  cent,  normal  saline  containing  car- 
bolic acid,  in  bottles  of  1  and  5  c.c.  The  original  solution  and  the  dilutions 
can  be  kept  practically  for  any  length  of  time  in  a  cool  place,  but  free  from 
frost  and  protected  from  light. 

N.B. — If  desired,  SBE  is  also  supplied  from  bacilli  of  the  typus 
bovinus. 

The   sensitized   bacillary   emulsion    is    used   subcutaneously. 

Contra-indications    are    cachexia,    mixed    infection,    and    lasting 

hectic  fever  caused  bv  the  latter. 
j 

The  treatment  is  begun  with  1  division  of  solution  6 

Dosage    of  SBE       (1  :  1,000,000)     and    the     dose    raised    according     to 

the  usual  principles,  noting  carefully  temperature, 

weight   and   general    condition   of   health.      Should   any    signs   of   febrile   or 

general  reactions  occur,  the  last  dose  injected  is  to  be  repeated. 

The  treatment  is  considered  to  be  ended  when  J  c.c.  of  the  stock  emulsion 
is  borne  without  reaction  and  the  clinical  result  is  satisfactory. 

_  According  to  the  extensive  investigations  of 

RpClll  +  C  ° 

Citron,  the  advantage  of  using  sensitized 
bacillary  emulsion  lies  in  the  fact  that  the  injections  produce 
less  fever  and  that  the  production  of  infiltration  is  reduced  to  a 
minimum.  Ed.  Meyer  and  Spiess  have  achieved  good  results 
with  this  preparation  in  the  treatment  of  laryngeal  tuberculosis. 
Cohn  observed  improvement  in  children  after  its  use.  Sawolsh- 
kaja  used  it  in  three  cases  with  good  results;  in  three  others  it 
had  to  be  given  up  because  it  produced  general,  local,  and  focal 
reactions.  According  to  Jochmann's  comparative  investigations, 
there  is  no  difference  in  the  clinical  effect  of  ordinary  and 
sensitized   bacillary   emulsion.      With    both   preparations    febrile 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        1 75 

reactions  could  be  avoided  with  caution  and  when  the  doses  were 
rapidly  increased,  both  produced  fever. 

We,  too,  have  for  some  years  made  extensive  use  of  sensitized 
bacillary  emulsion,  especially  in  the  more  advanced  cases.  We 
have  used  the  same  dosage  as  for  Koch's  bacillary  emulsion 
and,  when  the  length  of  treatment  permitted,  have  increased  up 
to  a  half  or  one  cubic  centimetre  of  the  original  solution  (cf. 
Chart  25).  We  have  seen  thoroughly  good  clinical  results  with 
the  preparation  and  can  confirm  the  advantages  claimed  by 
Citron.  We  have  not  yet  been  able  to  recognize  any  superiority 
over  Koch's  bacillary  emulsion,  either  as  regards  antipyretic 
action  or  in  respect  of  curative  power.  We  recommend  previous 
treatment  with  sensitized  bacillary  emulsion  and  as  soon  as  doses 
are  taken  from  the  original  solution,  Koch's  bacillary  emulsion 
should  be  substituted;  the  latter  is  also  considerably  cheaper. 
It  is  advisable  as  a  precautionary  measure  to  reduce  the  dose  to 
one-tenth  in  changing  from  one  preparation  to  the  other. 

Chart  25  shows  the  method  of  application  of  the  preparation 
in  a  case  of  tuberculosis  of  the  bronchial  glands,  febrile  for  three 
months,  with  closed  pulmonary  tuberculosis  of  the  first  stadium. 
Gradual  loss  of  fever  and  clinical  cure  were  effected  by  constant 
rise  of  dose  (even  rather  forced  in  the  case  of  the  larger  doses), 
with  but  one  febrile  reaction  towards  the  end  of  the  treatment. 

(6)  LANDMANN'S  TUBERCULOL. 

p  ..  Broth   cultures  of   highly   virulent  tubercle 

,   , ,     ,     ,  .  bacilli,  after  being  freed  from  fat  and  finelv 

and  Underlying  ,       ,  ,       .    ,      ..,  ,      ,.  J 

1     &    '  powdered,  are  extracted  with  normal  saline 

Principles.  or  diiute  glycerine  for  some  time  at  400  C. ; 

the  deposit  is  repeatedly  treated  in  the  same  way  with  fresh  fluid 

at  a  temperature  gradually  increased  from  500  to   ioo°  C.     The 

extracts  are  mixed  and  the  total  product  concentrated  in  vacuo  at 

37°  C.      By  means  of  this  fractional  extraction,   Landmann  [17] 

holds   that  all   the   toxins  contained   in   the   bacterial  bodies  are 

obtained    without    damage    or    appreciable    loss,    whether    those 

extracted  at  a  high  or  a  low  temperature.     The  insoluble  residue 

of  bacilli  remaining  behind,   when  suspended  in  water,   is,   even 

in    large   quantities,    incapable   of   killing   experimental   animals. 

On  the  other  hand,  the  preparation  itself  is  fatal  to  guinea-pigs 

in  a  dose  of  about  o"i  c.c.     The  latter  is  now  added  to  the  broth 

which   has  been   concentrated  in   vacuo   as   far   as  possible   and 

filtered;  the  mixture  is  again  filtered  through  procelain  candles, 

phenol   added  (5   per   cent.)   and   then    diluted   until    1    c.c.   is  a 

lethal  dose  for  a  guinea-pig  of  250  grm.     That  the  advantages 


176  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

of  this  original  method  are  not  merely  theoretical  is  shown  by 
the  fact  that  the  preparation  on  prolonged  heating  at  1000  loses 
its  action  and  1  c.c.  is  no  longer  a  lethal  dose  for  a  guinea-pig. 
This  tubercular  toxin,  containing  the  toxins 
of  the  culture  fluid  as  well  as  those  of  the 
perimes.  bacterial  bodies,  possesses  an  advantage  of 
no  small  magnitude — that  of  being  quantitatively  and  qualita- 
tivelv  tested  on  healthy  animals  and  the  dose  thus  exactly 
determined.  Landmann  adopts  the  point  of  view  that  tubercle 
bacilli,  like  diphtheria  bacilli,  form  genuine  bacterial  toxins,  that 
as  genuine  toxins  they  produce  in  the  animal  body  antitoxins 
and  expects  his  tubercular  toxin  to  form  antitoxins  by  means  of 
the  healthy  cells.  With  regard  to  the  test  of  toxicity  on  healthy 
animals,  he  is  opposed  to  Koch,  who  considers  the  peculiar 
characteristic  of  the  specific  tubercular  toxin  to  be  that  it  has 
no  effect  on  healthy  animals. 

In  a  series  of  experiments  Landmann  succeeded,  by  treating 
guinea-pigs  with  tuberculol,  in  immunizing  them  not  merely 
against  a  tenfold  lethal  dose  of  tubercle  bacilli,  but  in  curing 
with  injections  of  tuberculol  guinea-pigs  first  infected  with  double 
the  lethal  dose  of  bacilli.  The  control  animals,  without  excep- 
tion, died  of  advanced  tuberculosis  after  four  to  five  months. 

_..    .     .  In  man  the  method  of  treatment  is  the  same 

C,mical  -<-u     +u         +u  r  -a- 

as    with    the    other    preparations,    avoiding 

Application.  reactions   as   far   as   possible.      But   Land- 

mann lays  the  greatest  stress  not  merely  on  bringing  the  patients 
to  the  highest  level  of  immunitv,  but  on  keeping  them  there, 
i.e.,  prolonging  the  treatment,  and  we  concur  with  this.  He 
prefers  an  increase  of  one-half  and  only  reduces  this  to  one-third, 
one-quarter,  or  one-fifth  when  half  is  not  tolerated. 

The  doses  to  be  injected  would  be  then  as  follows  :  — 

Solution  (5)  :  (J,  |),  1,  ij,  2J,  3J,  5,  7!  divisions. 

Solution  (4)  :    1,   ij,  2J,  3J,  5,  7J  divisions. 

With  intervals  of  from  one  to  two  days. 

Solution  (3):   1,  ij,  2J,  3J,  5,  7J  divisions. 
With  intervals  of  two  days. 

Solution  (2)  :   1,  ij,  2 J,  3J,  5,  7J  divisions. 
With  intervals  of  from  two  to  three  days. 

T       Solution  (1)  :    1,    ij,   2J,  3J,  5,   7J,    10  divisions. 
With  intervals  of.  from  three  to  five  days. 

Repetition  of  the  maximal  dose  of  Solution  (1)  :   10  divisions, 
at  intervals  of  seven,  ten  and  fourteen  days. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  1 77 

With  experience  in  specific  treatment,  this  scheme  can  be 
modified  according  to  the  individuality  of  the  patient.  The 
maximum  dose  should  eventually  be  used  for  several  months 
until  its  highest  therapeutic  action  has  been  attained.  When 
necessary  a  second  course  of  treatment  can  be  begun  after  six 
months'  interval. 

Landmann    reports    good    results    in    open 
Kesults.  tuberculosis.     Frey  has  seen  in  some  cases 

better  results  than  with  other  tuberculins,  v.  Holten,  too,  claims 
that  tuberculol  (tuberculol  B,  containing  endotoxins)  exhibits  a 
greater  power  of  assisting  the  healing  of  the  pulmonary  tuber- 
cular process  than  old  tuberculin,  bacillary  emulsion  or  Beraneck's 
tuberculin.  Its  value  was  best  seen  in  severe  cases  and  after 
reaching  the  larger  doses.  Reactions  could  not  be  altogether 
avoided,  but  were  quite  harmless  when  once  the  higher  doses 
were  reached..  We  have  ourselves  employed  the  preparation  in 
a  large  number  of  cases ;  it  was  not  merely  very  well  borne  even 
where  a  tendency  to  severe  haemoptysis  was  present,  but  the 
patients  showed  a  considerable  retrogression  in  the  anatomical 
signs  of  disease,  were  obviously  better  and  increased  considerably 
in  weight. 

.  .  The    toxic    power    of    tuberculol    is    much 

°  Y  greater      than      that      of      old      tuberculin. 

u      rculol.  Patients  immunized  against  old  tuberculin 

still  react  to  divisions  of  solution  I  of  tuberculol.  It  is  there- 
fore a  more  difficult  and  lengthy  matter  to  immunize  against 
tuberculol.  But  we  have  not  been  able  to  prove  by  our  prolonged 
experiments  that  it  is  superior  in  its  curative  effect  to  Koch's 
preparations. 

Recently  the  two  components  of  tuberculol,  the  toxins 
secreted  into  the  culture  medium  and  the  extract  of  the  bacterial 
bodies,  have  been  separately  manufactured.  Landmann  has  also 
acceded  to  the  request  to  prepare  a  tuberculol  from  bovine  bacilli 
(Bovotuberculol). 

(7)  THE  TUBERCULIN  PREPARATIONS  OF  KLEBS. 

A  different  line  of  thought  from  Koch's  was 
Tuberculocidin.      fol]mved  by  Klebs  r-^g-j  in  the  procluctlon 

of  his  preparations.  He  believed  that,  besides  the  curative 
agent,  a  harmful  toxin  also  was  present  in  tuberculin,  which  he 
could  split  off  by  treatment  with  alcohol  and  bismuth.  This  was, 
then,  the  origin  of  his  first  preparation,  to  which  he  gave  the 
name  of  tuberculocidin  on  account  of  the  property  he  wished  to 
attain — the  destruction  of  the  bacilli. 
12 


178  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

As    his    tuberculocidin    was    not    yet    quite 

Antiphtnisin.  pure,    he  prepared   a   second   substance   by 

precipitating    the    filtrate    of    a    tubercle    culture    with    sodium 

bismuth-iodide  in  acetic  acid  and  absolute  alcohol,   and  to  this 

he  gave  the  name  of  antiphthisin  [177]. 

Assuming,  further,  that  every  case  of 
human  tuberculosis  is  a  mixed  infection,  he 
made  a  further  improvement  in  his  specific  treatment  by  isolating 
a  substance,  which  he  called  selenin,  from  the  Diplococcus 
semilunaris  (catarrhalis  of  Pfeiffer),  which  he  himself  discovered 
to  be  a  frequent  mixed  infection,  a  solution  of  the  bodies  of  the 
cocci  with  the  toxins  removed  by  H?02.  In  severe  cases  another 
immunizing  substance,  tuberculo-protein,  should  also  be  used. 

According  to  later  publications  [178],  the  indication  is 
generally  met  by  giving  by  the  mouth  3  c.c.  of  tuberculocidin- 
selenin  mixture  twice  a  day.  If  abundant  bacilli  are  present  in 
the  sputum  larger  doses  of  tuberculocidin  added  to  the  mixture 
are  advisable. 

More  recently  still,   Klebs  recommended  as 
Tuberculo-sozin.     &  seqUej   to   treatment  with  tuberculocidin- 

selenin,  which  should  in  all  cases  be  employed  first  until  the  limit 
of  its  action  is  reached,  his  newest  preparation,  tuberculo-sozin 
[179],  a  substance  obtained  from  dead  tubercle  bacilli  by  extrac- 
tion with  glycerine.  To  this  substance  he  ascribes  high 
immunizing  and  antipyretic  properties.  He  now  combines  the 
use  of  these  tuberculins  with  injections  of  tubercle  bacilli  from 
blind-worms  (cf.  pp.  197-198). 

Klebs  has  seen  favourable  results  from  his 
preparations  both  in  animals  and  tuber- 
cular patients.  Other  observers  have  not  confirmed  this  result, 
but  agree  in  finding  the  preparations  absolutely  harmless. 
Petruschky's  investigations  with  tuberculocidin  in  Koch's  Institute 
gave  a  negative  result;  Langermann's  were  unfavourable.  Better 
results  were  obtained  by  Gabrilowitsch,  Longstreet,  Taylor, 
Denison,  F.  A.  Elsasser,  Jessen  and  Pogue. 

(8)    BERANECK'S    TUBERCULIN    (TBk.). 

By  a  process  of  his  own,  Beraneck  [180]  prepared  a  tuber- 
culin which  should  contain  as  far  as  possible  all  the  substances 
having  immunizing  properties  whether  in  the  culture  fluid  or  in 
the  bacteria  themselves,  but  without  the  other  toxins  characteristic 
of  some  other  tuberculins  possessing  no  immunizing  power  and 
possibly  even  harmful. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  1 79 

It  is  composed  of  extracellular  toxins  of  the  broth 

Preparation    and      culture    of    special    formula    and    of    intracellular 

Dosaffe  toxins  extracted  from  the  protoplasm  of  the  bodies 

of  the  bacilli  with  i  per  cent,  phosphoric  acid  at 
a  temperature  of  60-700  C.  It  is  prepared  in  fifteen  different  dilutions,  the 
concentration  of  which  rises  in  powers  of  2  (not  of  10,  as  with  other  tuber- 
culins) ;  each  solution  is  therefore  double  the  strength  of  the  preceding  one. 
The  solutions  are  called  A/128,  A/64,  A/32,  A/16,  A/8,  A/4,  A/,,  A,  B,  C,  D, 
E,  F,  G,  and  H.  H  is  pure  tuberculin.  According  to  Sahli,  the  initial  dose 
is  usually  i  division  or  solution  A/3.,.  This  dose  is  repeated  two  or  three 
times.  If  a  reaction  should  occur,  i  division  of  the  solution  A/32  must  be 
given,  or  the  still  weaker  solutions  A/  ,  A/  8  employed.  Should  no 
reaction  occur,  each  injection  is  increased  by  i  division  up  to  a  dose  of  5 
divisions  of  A/  ,  which  is  repeated  several  times.  Then  one  passes  to  A/16, 
but  of  this  solution,  which  is  twice  as  strong,  one  only  injects  1  division 
and  then  increases  again  by  i  division  up  to  5  divisions  of  A/16.  This  dose 
is  also  repeated  several  times,  then  1  division  of  A/'g  is  injected,  rising  by 
i  division  up  to  5  divisions  of  A/g,  and  so  on.  As  soon  as  the  slightest 
reaction  occurs  the  dose  is  reduced  after  it  until  the  reaction  has  completely 
disappeared.  Generally  a  slight  reduction  is  sufficient  to  avoid  reactions;  it 
may,  however,  be  necessary  to  begin  the  treatment  again  from  the  initial 
dose.  Sahli  gives  the  first  injections  twice  a  week,  from  about  solution  E 
once  a  week,  and  when  the  maximal  dose  is  reached,  only  once  every  four- 
teen days.  With  good  tolerance,  the  usual  increase  of  dose  may  be  1 
division;  with  susceptible  patients  it  must  be  i  division.  In  this  way  in 
favourable  cases  the  maximum  dose  may  be  reached,  which  Sahli  considers 
to  be  10  divisions  of  the  pure  tuberculin  solution  H. 

This  tuberculin  has  been  warmly  recommended  by  Sahli, 
who  has  also  used  Koch's  old  and  new  tuberculin  as  well  as 
Denys',  and  gives  strong  preference  to  Beraneck's. 

With  regard  to  results,  he  states  that  certain  cure  may  be  reached  in  the 
slighter  cases;  often  only  a  state  of  equilibrium  between  disease  and 
organism  is  attained,  a  state  of  quiescence ;  in  a  third  category  of  cases  a 
degree  of  improvement  is  obtained,  but  such  marked  symptoms  remain  that 
even  compensation  of  the  tubercular  process  cannot  rightly  be  claimed; 
the  course  of  the  disease  remains  progressive,  but  it  has  been  prolonged. 

_,.    .     ,   „  Besides  Sahli,  others  have  given  a  favour- 

Clmical   Results.       .  ,  ■    ■  £     r> >  f>       .  1  i- 

able     opinion     ot     Beraneck  s     tuberculin, 

especially  Pischinger,  K.  Bauer,  Dluski,  Frankfurter,  E.  Bauer,. 

Kovacs,  and  others ;  also  Rollier,  Pallard,  Machard,  and  Mallet, 

in   cases  of   internal   and   surgical   tuberculosis.        Less   satisfied 

with  its  action  is  Amrein,  who  holds  the  tuberculins  of  Denys  and 

Koch  to  be  in  every  way  superior,   the  old  tuberculin  of  Koch 

vastly  so. 

From  the  existing  literature  Beraneck's  tuberculin  appears  to  be  pre- 
ferred principally   on   account    of   its    convenient   method    of    application,    a 


l8o  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

purely  external  reason  which  should  only  apply  where  tuberculin  is  infre- 
quently used. 

And  it  must  not  be  forgotten  that  solutions  of  tuberculin  lose  their 
efficacy  the  quicker,  the  more  they  are  diluted  and  the  longer  they  are  kept. 
On  this  account  we  recommend  the  physician  to  make  his  own  dilutions, 
a  very  simple  matter.  Moreover,  nothing  stands  in  the  way  of  the  other 
tuberculins  being  also  diluted  in  the  same  progression  by  the  user. 

(9)  CARL    SPEXGLER'S    TREATMENT    WITH    BOVINE 

TUBERCULIN. 

Attention  was  first  adequately  called  to  the  supposed  superi- 
ority of  the  immunizing  effect  of  bovine  tuberculin  on  human 
tuberculosis  by  Carl  Spengler  [181].  His  investigations  were  the 
result  of  Koch's  teaching  in  regard  to  the  specific  difference 
between  bacilli  of  human  and  bovine  origin.  Koch's  own  investi- 
gations had  shown  differences  between  the  living  cultures,  not 
between  their  products  of  secretion  and  cell  substances.  Spengler 
wrote  :  — 

,      ...  '"  The   toxins   of  bovine  tuberculosis   are   less   toxic 

bpengler  S    View    Oi     to  tubercular  man,  far  less  than  the  tuberculins  of 
Relation   between      human     tubercle     bacilli.       As      immunizing      and 
Human  and    Bovine    curatlve   agents   they   are   far   superior.      The  cura- 
tive  process    in    tuberculosis   under   their   influence 
Bacilli,  occurs  in  shorter  time,   and,  because  of  their  less 

poisonous  character,  safely  and  rapidly.  My  experiments  with  bovine 
toxins  in  man  and  those  first  of  Koch  and  then  of  v.  Behring  relating  to 
immunizing  cattle  with  human  tubercle  bacilli,  have  established  that  there 
exists  between  the  toxins  of  bovine  and  of  human  tubercle  bacilli  and  their 
hosts  a  reciprocal  antagonism  of  natural  origin,  in  the  sense  of  Jenners 
discovery.  The  two  originally  identical  infecting  agents  have  become  in 
their  respective  hosts  alternating  vaccines.  The  most  striking  result  of 
the  vaccinal  qualities  of  the  bovine  toxins  is  that  to  tubercular  man  they 
are  far  less  toxic  than  the  human  tuberculins,  although  the  bovine  bacilli 
show  themselves  more  virulent  to  animals."' 

~  .   .        j-  j..  Carl  Spengler  takes  up  the  dualistic  stand- 

Origin  of  the 

point  of  Koch.     With  his  school  he  further 

vine      acl    US-     assumes  that  a  progressive  infection  cannot 

be  produced  in  cattle  with  bacilli  of  human  origin,   nor  in   man 

with  bovine  bacilli ;  the  latter  contention  he  was  himself  the  first 

to  demonstrate  by  infecting  himself  with  J  mg.  of  living  bovine 

bacilli. 

His  view,  however,  is  that  the  bovine  bacillus  originated  from  man, 
a  view  in  part  supported  by  Kitasato's  researches  on  bovine  tuberculosis  in 
Japan,  confirmed  by  Deycke  for  Turkey.  He  holds  the  bovine  bacillus  to 
be  a  variety,  adapted  to  its  bovine  host,  of  a  bacillus  living  in  symbiosis 
with  the  human  tubercle  bacillus.  He  named  this  differentiated  bacillus 
Perlsucht  and  later  Bacillus  liumano-longus . 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  151 

According   to   his   bacteriological   researches  [182], 

Occurrence   Ot         ^e  Bacillus  humano-longus  in  the  majority  of  cases 

the   various  lives  in  symbiosis  with  the  short  tubercle  bacillus. 

r  A    smaller    percentage    rests    on    a    pure    tubercle 

bacillus    infection,    and    in    these    the    prognosis   is 

bad.     Rarest  are  the  cases  in  which  the  humano-longus  type  is  found  almost 

alone,  and  these  have  a  more  favourable  character.     The  unadapted  genuine 

bovine  bacillus  is  harmless  to  man ;  it  may  be  pathogenic  to  the  tubercular 

subject,  but  in  this  case  is  certainly  of  low  virulence. 

Schroeder  [183],  in  the  sputum  of  100  cases,  only  found  eleven  in  which 
bovine  bacilli  in  SjDengler's  sense  were  present.  In  ten  cases  the  sputum 
was  almost  non-toxic  in  rabbits.  The  inoculation  of  the  eleventh  sputum 
only  was  always  followed  by  a  severe,  fatal  form  of  tuberculosis  but  proved 
without  danger  for  cattle  [184].  In  contradistinction  to.  Carl  Spengler,  all 
cases  which  showed  in  the  sputum  the  characteristic  bovine  bacilli  belonged 
to  the  forms  of  human  phthisis  of  bad  prognosis. 

.       ..       .  These  studies  led  Spengler  to  develop  his 

L.   ,  ..  method  of  individual  tuberculin  therapy  in 

to  Tuberculin        accordance  with  the  etiological  factor  [185]. 

'  heraPy-  The  toxins  of  the   human   and   the  bovine 

bacilli  have,   like  the  bacilli  themselves,   an  antagonistic  action. 

For  tuberculin   treatment   that   preparation   must   first  be  chosen 

which  has  not  a  highly  toxic  action   and  which   least  depresses 

the  general  health.     This  substance  is  the  vaccine  and  originates 

from   that  variety  of  bacillus   which   is  not   predominant   in  the 

disease.     Only  later  on,   after  a  preliminary  immunizing  course 

with  the  vaccine,  is  the  employment  of  the  toxin  proper  admissible 

and  then  generally  advantageous. 

D      ....     ,  Confirmation    of    Carl    Spengler's    dualistic 

Bacilli   shewn  ,                .    .    .               ,         , 

_;„             ,  theory    ot     infection     has    been     given    by 

Different  by  the  r>        '       r  o^       u                j    1  •      \       ■ 

1  Donome  Lz°oJ?  wno  succeeded  in  showing  a 

Precipitin  Test,  tangible  difference  between  the  bovine  and 
human  bacilli  by  means  of  the  precipitin  method.  According  to 
his  results,  organic  extracts  of  human  tuberculosis  are  always 
agglutinated  in  respect  of  either  micro-organism,  whilst  the  extracts 
of  bovine  tuberculosis  give  neither  plural  agglutination  nor  plural 
precipitation.  Cultures  of  human  bacilli  injected  into  cattle  give 
little  or  no  bovine  agglutination,  but  a  very  marked  one  when 
injected  into  man.  From  these  sero-diagnostic  results  Carl 
Spengler  draws  the  conclusion  that  human  tuberculosis  cannot  be 
of  bovine  origin,  but  is  propagated  from  man  to  man  as  a  double 
infection.  Bovine  tuberculosis  originates,  like  all  other  infections 
of  domestic  animals,  from  man  ;  the  bovine  bacilli  are  a  variety  of 
the  symbiotic  Bacillus  humano-longus  of  man.  In  this  direction 
also  Koch's  dualistic  conception  receives  confirmation. 


l82  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

Carl  Spengler's  immunizing  substances  are 
Carl  Spenglers      ag    follows  .    ATO    (Alt-tub erkulin-original 

Immunizing  =  original    old   tuberculin)    consists   of    the 

Substances.  non-concentrated    culture    fluid    of    tubercle 

bacilli  of  human  origin  freed  from  bacilli  by  filtration,  i  c.c. 
corresponds  to  o-i  c.c.  of  old  tuberculin.  Initial  dose,  -ooooi 
to  'oooi  c.mm.  Maximal  dose  according  to  the  case.  Absolute 
maximum  1,000  c.mm. 

Vacuum  tuberculin  is  ATO  concentrated  to  one-tenth  of  its 
volume  at  a  low  temperature  under  reduced  pressure  :  I  c.c. 
corresponds  to  10  c.c.  ATO  or  i  c.c.  of  old  tuberculin. 

PTO  (Perlsucht-tub erkulin-original  =  original  bovine  tuber- 
culin) is  prepared  from  bovine  bacilli  in  an  analogous  way  to 
ATO.  i  c.c.  PTO  corresponds  to  o"i  c.c.  bovine  old  tuberculin. 
Initial  dose  '00001  to  "oooi  c.mm.  Maximal  dose  according  to 
the  case.     Absolute  maximum,  1,000  c.mm. 

Bovine  vacuum  tuberculin  is  PTO  concentrated  to  one-tenth 
of  its  volume  at  a  low  temperature  under  reduced  pressure. 
1  c.c.  corresponds  to  10  c.c.  PTO  or  Tec.  of  old  tuberculin. 

These  four  preparations  of  Carl  Spengler's  are  also  supplied  by  the 
Farbwerke  Hoechst  without  attaching  his  name  to  the  products  (cf.  pp.  163 
and  164). 

Tubercle  bacillary  emulsion  (TBE)  and  bovine  bacillary 
emulsion  (PE)  correspond  in  method  of  preparation  to  those  of 
Koch . 

To  supply  the  demand  for  substances  producing  a  toxic  and 
bacterial  immunity  based  on  the  antagonistic  working  of  the  two 
components  in  the  dualistic  etiology  of  tuberculosis,  Carl 
Spengler  originated  vaccines,  about  the  composition  of  which 
nothing  is  yet  exactly  known. 

PV  (bovine  bacillary  vaccine)  is  the  antagonist  of  ■  TBV 
(tubercle  bacillary  vaccine). 

Initial  dose  '000000001  to  '00000001  c.mm.  Maximal  dose,  according  to 
the  case,  i.e.,  the  dose  which  leaves  behind  a  swelling  slow  of  absorption  at 
the  site  of  injection,  avoiding  one  which  produces  abscess,  or  a  dose  which 
acts  toxically,  rendering  necessary  the  application  of  the  antagonist. 

TBV  (tubercle  bacillary  vaccine)  is  the  antagonist  of  PV 
(bovine  bacillary  vaccine). 

Application  as  under  PV.  Doses  may  be  injected  every  day  or  with 
longer  pauses  according  to  the  case.  As  a  rule  the  lower  doses  are 
increased  each  time  tenfold,  the  higher  doubled. 

If    the   immunizing    substance    be    not    well  borne  and    produces    toxic 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  I  ©3 

reactions,  e.g.  deterioration  of  health,  acceleration  of  the  pulse,  marked 
increase  in  the  quantity  of  sputum,  cough,  rise  of  temperature,  &c,  the 
antagonist  must  be  injected.  The  smallest  dose  is  given  to  start  with,  and 
on  increasing  it  the  toxic  action  of  the  vaccine  first  used  is  abolished^ 

Favourable  results  with  the  preparations  of 
Clinical  Results.  Cad  Spengler  are  recorded  in  recent  litera- 
ture by  various  observers  ;  thus  by  von  Brauns,  Friihwald,  Hollos, 
and  others,  v.  Szaboky  [187],  who  has  made  a  thorough  study 
of  Carl  Spengler's  method  and  all  investigations  pertaining 
thereto  for  a  long  time,  is,  however,  very  reserved  in  his  opinion. 
Moreover,  the  general  opinion  is  that  the  differences  in  the 
tinctorial  and  morphological  condition  of  the  tubercle  bacilli  in 
the  sputum  only  point  to  the  amount  of  variety  between  the 
tubercle  bacilli  of  the  typus  humanus.  In  the  same  way  the 
antagonistic  reactions  to  the  preparations  of  human  and  bovine 
origin,  which  were  supposed  to  enable  a  conclusion  to  be  formed 
as  to  the  etiology  of  the  exciting  cause,  have  hitherto  found  no 
acceptance. 

R      .  We  ourselves  have  used  bovine  tuberculins 

_   ,  ,.  .       (p.     164)    and    bovine    bacillary    emulsion 

Tuberculins  of       ;        ^  x  ,  .,      ir     ,    T     ...    ,     .         , 

(p.  173)  from  the  Koch  Institute  in  a  large 

Lower    I  oxicity.      number  of  cases  and  have  proved  that  the 

lower  toxicity  of   the   bovine   old  tuberculin,    as   compared   with 

tuberculin  made  from  human  bacilli,   is  absent  in  the  emulsions 

made  from  the  two  kinds  of  bacilli.     The  idea,  therefore,  occurs 

that  the  lower  toxicity  is  due  to  the  culture  broth  possessing  fewer 

toxins  of  the  bovine  bacilli,   owing  to  their  poorer  development 

in  culture  medium  used,  which  is  more  favourable  to  the  growth 

of  human  than  bovine  bacilli.     The  difference,  then,   in  toxicity 

would  be  quantitative  only  and  not  qualitative. 

According  to  Ruppel's  [172]  investigations,  chemical 
Ruppel's  analysis  of  many  bovine  stocks  has  shown  qualita- 

Exnprimpnts  tively  the  same  products  of  the  bacillary  body  as 

were  found  in  the  bacillus  of  human  type.  Not 
much  importance  can  be  attached  to  quantitative  differences  in  these  investi- 
gations, as  the  quantitative  proportions  of  the  various  substances  may  be 
subjected  to  relatively  severe  fluctuations  in  different  stocks  of  the  same 
kind  of  tubercle  bacilli.  In  his  experiments  on  animals,  Ruppel  was  unable 
to  prove  any  difference  in  action  between  the  two  forms  of  tuberculin. 

In  consideration  of  the  contradictory  results 

one  usions.         Q£  tjie  investigations  made  up  to  the  present 

as  to  the  difference  between  the  tuberculins  prepared  from  human 

and    bovine    bacilli    (R..    Koch,    Penrose,    C.    Spengler,    Kanda, 

de  Jong,   Wolback  and  Ernst,    Ruppel,    Bandelier),   Weber  and 


184  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

Dieterlen  [188]  have  worked  in  the  Sanitary  Board  with  tuber- 
culins of  equal  titre.  They  found  our  supposition  confirmed  that 
the  difference  in  the  toxicity  of  the  two  tuberculins  is  in  fact 
onlv  quantitative.  Experiments  on  cattle  and  guinea-pigs  gave 
similar  results  in  the  diagnostic  use  of  tuberculins  of  equal  titre. 

(10)  OTHER  TUBERCULINS  OX  THE  LINES  OF  KOCH. 

rt      .        r  The    ideas    underlvin?   the    preparation    bv 

Basis  of  .  i  ' ?    "1  i-  T7-     u>' 

various   workers   of  tuberculins   on    Koch  s 

various  other  ii.nes  tend,  in  the  main,  in  two  directions. 
Tuberculins.  On  the  one  hand,  the  protean  course  of 
tuberculosis  was  explained  not  only  by  the  varying  "  culture 
medium  "  of  the  tubercular  individual,  but  a  definite  significance 
was  ascribed  to  the  tubercle  bacillus  of  the  individual  case.  Then 
Koch's  old  tuberculin,  in  addition  to  the  secretions  of  the  living 
bacilli,  their  metabolic  products  and  portions  of  the  cell  bodies 
set  free  during  their  natural  destruction  and  by  extraction  during 
the  concentration  of  the  culture  broth,  also  contains  other  sub- 
stances derived  from  the  culture  medium  which  are  unimportant 
as  far  as  the  specific  action  of  the  tuberculin  is  concerned  (ex- 
tractive substances  from  the  meat,  peptone,  &c).  Other  investi- 
gators have  considered  these  non-specific  substances  to  be  less 
inert  than  Koch  and  have  sought  to  eliminate  them  by  various 
chemical  methods.  Working  on  both  these  lines,  various  other 
tuberculins  have  been  prepared  besides  those  already  described, 
but  all  based  on  Koch's  principles. 

Starting     from     the     assumption     that     the 
Tuberculin  varied   course   of   tuberculosis    is    not   suffi- 

from   Patients'       cientlv   explained   by   the   difference   in   the 
own   Bacilli  :          "  soil  "  of  the  tubercular  individual,  a  view 
Specific  Tuberculin,  supported    by    the    observation    that    appa- 
rently- the  most  similar  cases  behave  widely 
differentlv  in  their  relation  to  specific  treatment,  Krause  [189]  laid 
emphasis  on  the  fact  that  the  tubercle  bacillus  itself  here  plays 
the   principal    role,    the   more   so    as   cultures    of   equal    virulence 
on  the  same  medium  may  develop  quite  differently  under  the  same 
experimental  conditions.     Hence  he  believes  that  every  tubercular 
subject  houses  his  own  disease-producer  and  that  treatment  must 
be  conducted  with  tuberculin   produced  from   the  patient's  own 
bacilli,    and    for    this    purpose    he    prefers    a    specific    bacillary 
emulsion.     This  is  also  the  opinion  of  Hantjens  and  Rothschild; 
the  latter  bases  his  verdict  on  opsonic  tests  on  patients  so  treated. 
Prioritv,    however,    reallv    belongs    to    Lowenstein    [190],    who. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  1 85 

in  1905,  made  the  claim  for  the  "ideal  specificity''  and  placed 
it  on  an  experimental  foundation;  he  recommends  "that  tuber- 
cular patients  be  treated  with  tubercle  bacilli  grown  from  the 
case  in  question,  or  with  active  preparations  derived  from  them.'' 
Krause  gives  detailed  notes  of  several  cases  "successfully  treated 
thus,  but  himself  demands  a  strict  scientific  repetition  on  larger 
clinical  material. 

Apart  from  the  fact  that  such  a  method  is  impracticable  on 
a  large  scale,  it  seems  to  us  further  not  well  grounded  in  theory. 
And  the  cases  cited  do  not  seem  designed  to  prove  its  superior 
value. 

,..  ,,  The     same     may     be     said     of     the     Auto- 

Tuberculin   of   Rothschild   [191],   based  on 
Mixed  tjie  same  conception.   He  does  not  recognize 

Tuberculin.  anv    difference    in    principle    between    the 

numerous  tuberculins,  and  considers  his  treatment  with  auto- 
tuberculin  to  be  the  ideal  form  of  application.  But  as  this  pro- 
cedure now  seems  to  him  impracticable  on  account  of  its  practical 
difficulties,  he  thinks  he  has  found  a  solution  of  the  problem 
in  his  mixed  tuberculin.  It  is  a  mixed  tuberculin  composed  of 
as  many  varieties  as  possible  of  the  typus  humanus,  a  polygenous 
bacillary  emulsion.  He  assumed  that  in  this  way  it  was  extremely 
probable  that  specific  protective  bodies  would  be  formed  against 
that  variety  of  tubercle  bacilli  from  which  the  patient  happened 
to  be  suffering.  Out  of  eighty-two  cases  of  tuberculosis,  some 
of  which  were  serious,  he  cured  forty-seven.  In  laryngeal  tuber- 
culosis, too,  this  modification  of  the  bacillary  emulsion  has  proved 
efficacious. 

F.  Rosenfeld,  in  an  excellent  treatise  [192],  in  which  he  declares  himself 
to  be  a  convinced  believer  in  tuberculin,  tells  us  that  he  has  treated  twenty- 
five  cases,  some  of  which  were  exceptionally  difficult,  with  good  results  with 
this  mixed  tuberculin.  He  does  not  assert,  however,  that  the  same  results 
could  not  have  been  attained  with  Koch's  bacillary  emulsion. 

...   ,~-,_.  ,         Wolff-Eisner  recommends  a  combination  of 

W olTr-E.isner  s 

old  and  new  tuberculin,  made  according  to 

Mixed  Tuberculin   hig  directions?  and  which  he  caljs  <<  Mixed 
('  +  TR).  Tuberculin,"    a    name    already    chosen    by 

Rothschild  for  his  polygenous  bacillary  emulsion.  Wolff-Eisner 
considers  this  combination  a  very  simple  but  satisfactory  solution 
of  the  complex  question,  of  which  preparation  is  the  most  appro- 
priate for  tuberculin  treatment.  Information  as  to  the  results 
of  the  use  of  this  mixture  is  not  to  hand,  but  only  persistent 
claims  for  its  value. 


1 86  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

We  consider  this  combination  very  simple  but  not  a  happy 
one.  Many  patients  tolerate  old  tuberculin  better  than  bacillary 
emulsion;  with  others  the  reverse  is  the  case.  Susceptibility  to 
one  part  of  the  preparation  may  prevent  immunization  against  the 
other  substances  it-  contains.  Such  observations  have  already 
been  made  by  Jochmann.  The  obvious  endeavour  to  immunize 
to  as  many  substances  in  the  tubercle  bacilli  as  possible  led  us 
(and  after  us  Koch  and  Jochmann)  in  cases  which  were  very 
susceptible  to  the  bacillary  emulsion  to  treat  first  with  old 
tuberculin  preparations,  after  which  immunization  to  the  former 
was  much  more  quickly  achieved. 

Denys       [193]      filtered     tubercle     cultures 
Denys'  Tuberculin  ;  through  porcelain  and  avoided  boiling  the 
filtrate,   assuming  that   useful   toxins  were   thereby   destroyed. 

Denys'    tuberculin    then    contains,    besides    toxins 

Based    On    Animal     secreted  by  the   living  bacilli,   only  those  proteids 

Experiment  from   the  dead  bacteria   which   go   into   solution   in 

the    culture     fluid,     whilst     the    insoluble    proteids 

which    remain    in    the    bacterial    bodies    do    not    come    into    action.     Denys 

injected    healthy    dogs    with   his    tuberculin    in   increasing    doses,    with    the 

result  that    a    subsequent   infection    with   a    lethal    dose    of   tubercle   bacilli 

produced  no  signs  of  disease.     On  treating  dogs  which  had  previously  been 

infected  some  survived,  and  in  others  a  distinct  inhibiting  influence  on  the 

disease   could  be  noted,  and   some  retrogression  of  the  morbid   changes  in 

comparison     with     control    animals.     Also     goats    previously    treated     with 

Denys'  tuberculin   stood  a   subsequent  infection   with  living  tubercle  bacilli 

without  harm. 

The  animal  experiments  seem  somewhat  scanty,  a  fact  which  Denys 
justifies  on  the  ground  of  expense  and  because  analogous  action  in  the 
tubercular  human  subject  does  not  necessarily  follow. 

He  then  employed  his  preparation  with  good  result  on  man.  His  own 
experience  extends  over  more  than  2,000  cases  which  he  has  treated  himself 
or  indirectly  through  other  practitioners. 

r-,  .      .    .  r         The   principle   of    Denvs'    treatment   is   the 

Principles  or 

mildest  form  of  administration,  avoiding  all 

=>   "  marked  reaction,  in  which  term  he  includes 

not  merely  fever  but  other  general  disturbances.     He  considers 

febrile  reaction  not  merely  unnecessary,  but  an  actual  hindrance 

to   the    occurrence    of    immunity   as   well    as    dangerous    for    the 

patient.     The  maximal  dose  is  determined  according  to  individual 

tolerance.     In    contrast    to    Petruschky's    interrupted    method    of 

treatment,  he  considers  it  necessary  to  keep  up  the  tox-immunity 

for  as  long  as  possible  in  order  to  give  the  organism  time  for 

the  healing  processes.     During  treatment,  pulse  and  body-weight 

are  specially  to  be  considered ;  fever  is  no  contra-indication. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  1 8/ 

We  have  already  pointed  out  that  Denys'  tuberculin  is 
nothing  else  but  Koch's  non-concentrated  tuberculin,  his  original 
tuberculin.  In  consequence  of  its  wide  use  on  the  Continent, 
it  is  now  also  prepared  in  Germany.  In  speaking  of  original 
tuberculin  (TOA)  we  have  already  said  that  we  cannot  demon- 
strate any  superiority  of  this  preparation  to  Koch's  old  tuberculin. 
Moreover,  a  critical  examination  of  the  literature  available  (for 
example,  that  of  Schnoller,  P.  C.  F.  Koch,  Amrein,  Kersbergen) 
can  lead  to  no  other  conclusion. 

_   ,    .,       .       ...        Gabrilowitsch's    endotin,    according    to    his 
Gabnlowitscn  s  ...  , 

experiments    on    animals,    is    supposed    to 

Endotin.  possess    all    the    valuable    specific    qualities 

of  Koch's  old  tuberculin  without  causing  violent  reactions. 

It  is  made  in  a  similar  manner  to  Koch's  prepara- 
Preparation.  ti°n    from    tubercle   bacilli   of  the    typus   humanus. 

After  previous  treatment  with  alcohol,  xylol,  ether 
and  chloroform,  followed  by  decanting  and  centrifugal  processes,  it  is 
finally  treated  with  hot,  diluted  lye,  to  separate  the  by-products  contained 
in  old  tuberculin  (fats,  carbohydrates  and  albumen)  which  cause  general 
reactions,  but  have  no  curative  effect.  High  fever  is  supposed  to  be  no 
contra-indication  as  it  is  to  Koch's  old  tuberculin.  Initial  dose,  o'oi  c.mm.  ; 
maximum  dose,  200  c.mm. 

Gabrilowitsch     [194]     reports     good     results     and 

Conflicting  describes  the  preparation  as  a  powerful  remedy  for 

Estimates    of  its      tuberculosis.       In    a    treatise    emanating    from    his 

»,    I  sanatorium,  Kurdjumoff  has  recently  recommended 

it  for  the  treatment  of  latent  tuberculosis  and 
phthisis  incipiens  of  children  over  10  years  of  age.  As  objective  improve- 
ments he  cites  a  favourable  influence  on  raised  temperature  and  on  tuber- 
cular glands  in  the  neck.  The  efficacy  of  the  preparation  is  confirmed  by 
Bandevin,  Blumenau,  Bbhm,  Deal,  Gordon,  Helms,  Hirschberg,  Iwanow, 
Lapschin,  Masing,  Michailowa,  Rostoschinsky,  Slatowerkownikow.  W. 
Neumann  prefers  it  to  all  other  tuberculins.  Horol,  Gaikowitsch,  and  Vos 
have  not  observed  any  superiority  to  Koch's  tuberculins.  According  to 
Curschmann's  and  Walterhofer's  observations  on  twenty-five  patients,  not 
only  was  there  no  good  effect  whatever,  but  in  many  cases  the  condition  of 
the  lung  changed  for  the  worse.  Gordon  [195]  tried  with  much  emphasis,  but 
not  with  convincing  logic,  to  prove  to  the  Scientific  Congress  in  Konigsberg 
in  1910  that  endotin  was  the  one  and  only  active  substance  of  tuberculin. 
He  overestimates  the  quantity  of  non-specific  substances  which  are  supposed 
to  be  injurious  in  Koch's  old  tuberculin,  which  are,  it  is  true,  not  absolutely 
indifferent,  but  need  not  be  considered  on  account  of  their  small  quantity. 
Moreover,  old  tuberculin  produces  no  toxic  symptoms  when  used  in  high 
dilutions.  The  difference  between  endotin  and  old  tuberculin  is  presum- 
ably quantitative,  not  qualitative.  Gordon's  attempt  to  explain  the  febrile 
reaction  caused  by  the  tuberculins  hitherto  used  as  the  effect  of  albumose 
is  quite  a  mistake  and  long  ago  refuted. 

Landmann  remarked  in  the  discussion  at  the  above  lecture  that  it  was 


1 88  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

impossible  from  a  chemical  point  of  view  to  remove  the  albumose  from  the 
tuberculin  according  to  the  methods  described;  he  considers  its  separation 
generally  impossible.  Gordon's  published  results  are  very  good ;  but  no 
such  enthusiastic  verdict  has  been  received  up  to  the  present  from  any  other 
quarter,  not  even  from  Gabrilowitsch  himself.  And  in  reference  to  the 
assertion  that  endotin  never  produces  fever,  and  that  fever  in  cases  of 
advanced  phthisis  is  no  contra-indication,  it  must  be  mentioned  that  accord- 
ing to  Masing  all  Russian  physicians  who  have  had  much  experience  with 
endotin  cease  the  treatment  when  the  evening  temperature  exceeds  38" 50  C. 

Also,  according  to  the  scanty  information  of  recent  German  literature, 
endotin  produces  febrile  reactions  even  with  cautious  dosage,  so  that  it 
does  not  deserve  to  be  described  as  pure  or  non-toxic  tuberculin.  The  pro- 
blem of  how  to  isolate  and  purify  the  specific  substance  from  the  tubercle 
bacilli  for  purpose  of  immunization  is  as  yet  unsolved,  although  it  has 
been  ceaselessly  studied  ever  since  the  discovery  of  tuberculin.  According 
to  Jochmann's  and  Mollers  investigations,  endotin  is  certainly  free  from 
albuminous  substances,  but  at  the  same  time  the  specific  substance  is  con- 
siderably injured,  as  even  100  c.mm.  of  endotin  is  not  sufficient  to  kill  a 
tubercular  guinea-pig  (in  contrast  to  the  fatal  dose  of  5-10  c.mm.  of  old 
tuberculin),  and  because  the  preparation  in  the  concentration  on  the  market 
contains  no  substances  which  can  be  proved  either  by  fixation  of  comple- 
ment or  by  the  precipitin  method  to  have  a  specific  action. 

Also,  according  to  Hinze's  experiments,  endotin  contains  but  very  small 
quantities  of  tuberculin,  for  only  in  the  most  sensitive  patients  could  he 
obtain  a  positive  cutaneous  reaction  with  the  strongest  solutions,  and  this 
even  was  much  less  severe  than  that  obtained  with  the  higher  dilutions  of 
old  tuberculin. 

Endotin  is  therefore  not  a  progressive  step  in  specific  treat- 
ment and  has  nothing  in  common  with  Koch's  albumose-free 
tuberculin,  except  the  absence  of  albumose. 

_  ,  Calmette  brings  an  article  into  the  market 

under  the  name  of  Tuberculin   CL,   which 

Tuberculin    (CL).     he  consjjers   essentially  different   from  the 

tuberculins  hitherto  produced  in  action,  strength,  and  effect.  The 
points  of  difference  and  advantage  lie  in  the  strong  concentration, 
the  slight  toxicity  and  the  striking  fact  that  fever  never  occurs 
and  the  rise  of  the  opsonic  index  shows  the  curative  result.  Little 
is  known  as  to  the  efficacy  of  the  preparation  from  other  quarters. 
Ribera  y  Sans  tried  it  in  six  cases  of  tuberculosis  of  the  joints, 
and  not  only  noticed  no  improvement  in  the  local  infection,  but 
a  most  unfavourable  effect  on  the  general  health. 

Tuberculin    CL    is     supposed    to    contain    all     the 

Composition    and     secretions   produced   by  the   tubercle   bacilli   in   the 

Dosaffe  cultures,  as  well   as  the   protoplasmic   substance   of 

the  bacillary  bodies   extracted  in   vacuo  by  means 

of  glycerine,   capable  of  precipitation  in  the  cold  by  absolute   alcohol,   not 

capable  of  dialysis  by  ether,  soluble  in  normal  saline.      It  is  supposed  to  be 

ten   times    stronger   than   the   preparation    which    is   precipitated   by  alcohol 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  1 89 

from  cultures  of  tubercle  bacilli  sterilized  by  heat  and  a  thousand  times 
stronger  than  Koch's  old  tuberculin  containing  glycerine.  Its  strength  is 
ascertained  by  the  determination  of  the  lethal  dose  by  intercerebral  injection 
in  healthy  guinea-pigs;  this  dose  amounts  to  8-10  c.mm.,  in  contrast  to  8  c.c. 
of  old  tuberculin.  It  is  injected  in  increasing  doses  of  o'oooi  to  1  c.mm.  at 
intervals  of  twelve  days  for  a  long  time ;  generally  twenty-four  injections 
are  required  to  complete  a  cure.  But  it  must  be  pointed  out  that  inter- 
cerebral injection  as  a  test  for  toxicity,  also  used  by  v.  Lingelsheim,  has 
been  already  abandoned  in  Germany  because  it  offers  too  little  guarantee 
for  the  specificity  of  the  effect.  So  that  according  to  Koch  the  test  of  tuber- 
cular toxins  on  healthy  animals  must  be  rejected  as  unsuitable,  because  it 
cannot  serve  as  a  measure  for  the  quantity  of  specific  substance  contained 
in  a  preparation;  for  it  is  just  the  peculiar  characteristic  of  the  tubercular 
toxin  that  it  exhibits  its  toxic  action  only  in  a  tubercular  and  not  in  a  sound 
organism.  Moreover,  in  testing  tuberculins  it  must  be  proved  that  the 
preparation  possesses  the  power  of  producing  in  the  tubercular  organism 
the  anatomical  changes  which  are  typical  of  a  tuberculin  reaction  (Ruppel). 

_  ,  ,  The    latest    modification    of    tuberculin     is 

Rosenbach  s         7->         ,      ,,       .   ,  ,.      r     ,--,        c       ,  •  u 

Rosenbach  s     tuberculin    L196J,     01     which 

Trichophyton        Rosenbach  says  that  it  arises  through  bio- 
Tuberculin,  chemical  processes  in  the  growth  on  living 
tubercle    bacilli    and    their    culture    medium    of    a    hyphomycete 
which  flourishes  in  living  human  and  animal  tissue.     This  is  the 
Trichophyton  holosericum  album  first  described  by  him. 

The  trichophyton,  according  to  Rosenbach,  is  easily  developed  in 
cultures  of  tubercle  bacilli.  It  grows  luxuriantly  in  the  culture  in  large 
patches,  partly  as  threads,  partly  as  a  widespread  network.  After  the 
trichophyton  has  grown  for  some  time  the  tubercle  bacilli,  according  to 
Rosenbach,  show  modifications  plain  to  the  naked  eye,  which  are  betrayed 
by  a  darker  colour  and  decay  of  the  zooglcea,  and  under  the  microscope  are 
clearly  seen  as  involution  forms  of  the  bacilli.  The  changes  brought  about 
in  the  culture  medium  by  the  trichophyton  fungus  were  not  only  on  the 
surface  but  throughout  the  culture.  Rosenbach  supposes  that  the  whole  of 
the  tubercle  bacilli  culture  is  affected  by  the  fungus  in  such  a  way  that  the 
toxic,  less  stable  molecular  body  is  changed  or  destroyed,  whilst  the  more 
stable,  immunizing,  antitoxin-forming  elements  remain. 

Rosenbach   prepares   the   tuberculin    in    the 
Preparation.         following  way  ._ 

Particles  of  the  trichophyton  fungus  are  added  to  cultures  of  tubercle 
bacilli  from  six  to  eight  weeks  old.  At  a  temperature  of  20-220  C.  this 
fungus  develops,  and  after  ten  to  twelve  days  has  covered  the  greater  part 
of  the  culture  of  tubercle  bacilli  with  a  white  mycelium.  Then  the  mass 
(tubercle  bacilli  and  fungus  culture)  is  separated  from  the  culture  medium, 
mixed  with  a  solution  of  glycerine  and  carbolic  acid,  ground,  filtered  and 
added  to  the  filtered  culture-fluid.  The  volume  is  increased  to  just  ten 
times  that  of  the  original  culture-mass  (tubercle  bacilli  and  trichophyton), 
and  to  preserve  the  tuberculin  an  addition  is  made  of  5  per  cent,  of  carbolic 
acid. 


1 90  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

.      _  In    surgical    tuberculosis     it     is     employed 

Use  in  Surgical      locally  and  subcutane0Usly.    Local  injection 
Tuberculosis;        assures  energetic  action   of  the  tuberculin, 
Locally  :  ancj   [s   preferable   in   all   cases   where   it   is 

practicable.  In  closed  foci  it  should  be  injected  as  near  the  centre 
of  the  foci  as  possible,  where  there  is  a  tubercular  space.  In  open 
foci,  the  injection  of  the  tuberculin  into  the  tubercular  spaces  and 
fistula?  only  results  in  focal  and  general  reaction  without  per- 
ceptible healing  action  ;  the  latter  is  only  observed  after  injection 
into  the  walls  and  floor  of  the  focus,  but  care  must  be  taken  that 
it  does  not  escape  and  become  useless  by  means  of  the  granulation 
or  fistula?.  The  various  surgical  measures,  such  as  incision, 
drainage,  dressing,  rest,  or  movement  of  joints,  &c,  must  be 
observed. 

The  subcutaneous  method  is  limited  to  cases 
Subcutaneously.  Qf  surgicai  tuberculosis,  where  the  foci  can- 
not be  reached  by  local  injection  (tuberculosis  of  the  vertebra?, 
inaccessible  glands,  peritoneum,  &c).  Its  action  used  thus  is  not 
so  striking.  The  curative  action  is  certainly  not  to  be  under- 
estimated and  is  lasting  in  the  case  of  closed  foci  {e.g.,  tuber- 
culosis of  vertebra?),  but  it  is  more  or  less  ineffective  in  the  open 
forms,  especially  if  there  are  secondary  causes  of  suppuration. 
The  subcutaneous  method  is  also  the  only  one  applicable  to 
pulmonary  tuberculosis. 

.,  .  Rosenbach    emphasizes    that    a    focal    and 

Va,ue  1  «.■  ■  -c    *U       4.    u 

general   reaction   is   necessary  it   the  tuber- 
of  Reaction.         culin  ig  tQ  be  effective ;   it  should  reach  a 

considerable  but  not  extreme  degree.  He  states  that  he  has  never 
observed  harmful  effects  nor  the  formation  of  new  foci  as  a 
result  of  the  reactions,  which  are  both  of  curative  value  and 
absolutely  essential.  Non-tubercular  individuals  tolerate  the 
tuberculin,  according  to  his  experiments,  in  fairly  large  doses 
without  disturbance  of  the  general  well-being.  It  can  also  be 
employed  in  diagnosis ;  reaction  is  evident  as  infiltration  at  the 
place  of  injection  and  subsequent  rise  of  temperature.  Rosenbach 
gives  the  following  technique  for  the  injections  :  — 

In   therapy   the   injection   of   the    tuberculin   should 

Rosenbach's  be    made    into    the    focus    itself  in    all    cases  where 

km    ,i        i  this    is    possible.      Subcutaneous    injection    may    be 

indicated  alone  or  in  addition  to  local  employment, 
where  other  tubercular  affections  are  present  inaccessible  to  the  local  method, 
or  also  at  the  commencement  of  treatment  in  order  that  the  reaction  to  the 
first  injections  into  the  tissue  itself  may  be  milder.  The  initial  dose  sub- 
cutaneously was  almost  always  200  c.mm.,  even  with  the  smallest  children. 
Only  where  a  test  injection  showed  special  susceptibility  was  the  dose  corre- 
spondingly  reduced.      This    dose    was    raised    in    the    subsequent    injections, 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  191 

generally  by  100  c.mm.  each  time,  but  in  many  cases  not  so  frequently,  and 
sometimes  a  smaller  increase  was  made  according  to  the  reactions  and 
condition  of  the  patient.  The  interval  between  the  injections  was  chiefly 
governed  by  the  reaction,  also  by  the  condition  of  the  patient  and  size  of 
dose.  Small  doses  without  perceptible  reaction  were,  since  they  were  too 
small,  often  repeated  on  the  following  day,  those  with  considerable  reaction 
in  three  to  seven  days  and  those  with  very  severe  reaction  in  eight  to  ten 
days.  Particularly  with  the  larger  doses  towards  the  end  of  treatment,  a 
pause  of  fourteen  days  was  often  necessary.  In  addition  to  the  cessation 
of  the  reaction,  nutrition  is  often  to  be  considered  in  determining  the  time 
of  repetition,  for  the  appetite  may  be  considerably  reduced  in  moderate 
reactions  for  one  or  two  days,  in  severe  reactions  longer.  When  no  reactions 
occur  to  the  higher  doses  the  treatment  is  finished. 

Judging  by  the  histories  of  the  patients,  we 
A  Case  of  hold  that  the  results  do  not  prove  a  superior 

Weakened  Tuber-  healing  action  to  that  of  the  most  used  tuber- 
culin Action.         culins.    Considered  impartially,  one  gets  the 

impression  from  the  cases  treated  sub- 
cutaneously  that  it  is  a  case  of  weakened  tuberculin  action.  The 
intrafocal  treatment  in  suitable  cases  of  surgical  tuberculosis  of 
glands  and  lupus  is  more  individual,  though  the  principle  is  not 
new.  This  method  of  treatment  with  proved  successes  in  a  large 
number  of  cases  is  possibly  the  most  important  part  of  Rosen- 
bach's  experiments ;  the  method  was,  however,  previously  used 
by  Lenzmann  in  surgical  tuberculosis  (c/.  p.  266),  who  used  old 
tuberculin.  We  are  inclined  to  attribute  these  successful  results 
not  to  Rosenbach's  tuberculin,  but  to  the  method.  The  latter  is, 
indeed,  not  a  new  one,  but  had  been  practised  for  many  years 
in  lupus  with  Koch's  tuberculin  (cf.  p.  259) ;  and  the  effect  was 
exactly  similar  to  that  observed  by  Rosenbach.  We  repeat  that 
the  results  published,  both  local  and  general,  give  the  impression 
of  weakened  tuberculin  action,  which  would  only  be  expected 
considering  the  mode  of  preparation  of  the  tuberculin.  There 
seems  to  be  no  sufficient  proof  of  a  specific  bio-chemical  influence 
of  the  trichophyton  fungus  on  the  tuberculin. 

Seyberth  has  treated  ten   cases  of   localized   tuber- 
txperiences  culosis   with   this   tuberculin,    of  which   eight    were 

with    Rosenbach's    much  improved  locally  and  generally. 

Tuberculin  ^'     Curschmann's    successes    in    pulmonary    tuber- 

culosis of  various  stadia  were  very  encouraging. 
A  case  of  tubercular  periostitis,  which  was  treated  not  with  local  but  intra- 
muscular injections,  showed  clinical  cure  in  five  weeks;  a  case  of  caries  of 
the  metatarsal  bones  was  not  influenced.  On  the  ground  of  further  experi- 
ences, he  recommends  the  preparation  also  for  children  and  particularly  for 
febrile  patients,  as  he  considers  its  antipyretic  action  and  the  improvement  of 
local  symptoms  in  cases  of  favourable  prognosis  quite  apparent  and  very 
prompt.     He  emphasizes  the  relative  insignificance  of  the  focal  reactions. 


I92  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

According  to  experiences  in  the  First  Medical  Clinic  in  Berlin,  pub- 
lished by  Kohler  and  Plaut  [197],  the  tuberculin  is  to  be  regarded  as  an 
active  remedy  for  pulmonary  tuberculosis.  Of  thirty-four  cases,  8s-4  per- 
cent, had  a  positive  result;  the  objective  pulmonary  symptoms  disappeared 
in  4i'2  per  cent,  and  also  increase  of  weight,  disappearance  of  fever  and 
improvement  of  the  subjective  symptoms  were  observed.  These  results  were 
obtained  not  only  with  patients  in  the  first  stadium  but  also  with  many  in 
the  second,  chiefly,  however,  with  slight  cases. 

Still  more  favourable  are  the  results  of  Stolzenburg  [19S]  in  a  series 
of  twenty  severe  cases.  Two  tolerated  the  preparation  as  badly  as  other 
tuberculins.  In  one  the  result  was  practically  nil,  in  two  but  slight. 
Fifteen  showed  very  considerable  objective  improvement;  ten  lost  the 
bacilli  from  the  sputum. 

Schaefer  [199],  on  the  contrary,  observed  no  special  action  of  the  pre- 
paration in  thirty-four  pulmonary  cases,  of  which  two  also  had  surgical 
tuberculosis ;  he  obtained  the  impression  that  by  the  action  of  the  tricho- 
phyton the  tuberculin  had  entirely  lost  its  specific  character.  He  was  also 
always  unsuccessful  in  producing  a  positive  cutaneous  reaction  with  the 
preparation. 

Koch,  also,  never  obtained  success  with  it. 


Ditthorn  and  Schultz  [200  and  201],  from 
old    tuberculin,     from     watery    extracts    of 
Tuberculin.  washed    bacilli    arising    in    old    tuberculin 

cultures,  from  fresh  tubercle  bacilli  or  bacilli  freed  from  fat,  also 
from  culture  fluids  separated  from  bacilli,  obtained  precipitates 
with  basic  iron  chloride ;  these,  after  removal  of  the  chlorine  and 
albumin  by  washing  with  sterile  water,  gave  clear  solutions  in 
very  dilute  caustic  soda.  These  iron  tuberculins  (which  contain 
considerablv  less  non-specific  but  not  indifferent  albuminous 
substances  than  old  tuberculin)  have  proved  of  utility  in  their 
diagnostic  and  therapeutic  experiments;  general  toxic  symptoms 
were,  as  a  rule,  considerably  reduced,  and  in  many  cases  great 
local  improvement  was  seen. 

D  According    to    Schellenberg    [63]    "  iron   tuberculin 

P  '  A "    prepared    from    old    tuberculin    bears    a    close 

relation  in  action  and  usefulness  to  the  albumose-free  preparation  :  general 
and  febrile  reactions  are  less  frequent  and  milder  than  with  old  tuberculin ; 
the  larger,  more  active  doses  can  be  relatively  quickly  reached  without 
severe  febrile  reactions;  the  clinical  results  are  good  and  are  not  inferior 
to  those  obtained  with  other  preparations ;  iron-tuberculin  is  especially 
suited  for  ambulant  treatment  on  account  of  the  very  slight  accompanying 
symptoms. 

Amrein  [202]  finds  that  iron  tuberculin  A  is  better  borne  than  old 
tuberculin  and  permits  of  quicker  rise  to  large  doses,  but  is  less  valuable 
as  regards  therapeutic  activity.  In  the  cases  unsuccessfully  treated,  aggra- 
vation of  the  condition  was  not  observed.  Amrein  recommends  it  for  cases 
which  need  special  caution  in  tuberculin  treatment. 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        1 93 

Cantani  [203]  observed  an  antiseptic  action 
of  iodine  on   tubercle  bacilli  and  also  be- 
T uberculin.  lieves  in  its  antitoxic  action  in  tuberculosis. 

He  is  of  opinion  that  the  internal  application  of  iodine  neutralizes 
the  febrile  action  of  tuberculin,  without  affecting  its  specific 
properties.  He  has  therefore  rendered  cultures  of  tubercle  bacilli 
non-toxic  by  means  of  iodine  and  has  prepared  an  iodized  tuber- 
culin which  produces  no  febrile  reaction. 

Marchesini  and  Pende  have  made  experiments  in  guinea-pigs  infected 
with  tuberculosis,  using  a  combination  of  old  tuberculin  and  iodine 
("Sierosin"  prepared  by  Sbarigia),  and  found  that  in  the  lungs,  glands, 
spleen  and  liver  the  most  varying  degrees  of  fresh  formation  of  connective 
tissue  could  be  recognized;  especially  in  glandular  tuberculosis,  complete 
anatomical  healing  was  observed. 

Turmann   [204]   has  had  a  preparation  similar  to  Cantani's 
made  by  Merck  and  Co. 

It  is  supposed  to  be  a  chemical  combination  of  iodine  and  the  albuminous 
substances  of  tubercle  bacilli  and  to  have  a  favourable  action  on  experi- 
mental tuberculosis  in  animals.  This  recalls  the  work  of  Leonardo  in  the 
Duranto  Clinic  at  Rome;  he  sought  to  explain  the  favourable  action  of  iodine 
on  the  tubercular  process  by  the  fact  that  the  iodine  treatment  raised  the 
opsonic  index.  Iodine  is  retained  in  tubercular  foci  for  about  four  days, 
whereas  in  other  inflamed  foci  it  is  no  longer  demonstrable  after  twenty-four 
hours.  By  this  means  a  number  of  leucocytes  and  an  increased  quantity  of 
protective  substances  are  found. 

Owing   to  the  very  favourable  experiences 

Arsenical  of    Benario    with    regard    to   the    increased 

Tuberculin.  curative   effect   of   new  tuberculin   bacillary 

emulsion  when  accompanied  by  subcu- 
taneous injections  of  sodium  arsenate  (Fowler's  solution),  the 
Hoechst  Farbwerke  have  produced  an  arsenical  bacillary  emulsion. 
For  this  purpose  they  bred  tubercle  bacilli  of  the  typus  humanus 
on  culture  fluids  containing  arsenic,  and  by  gradual  systematic 
increase  in  the  additions  of  arsenic  finally  produced  tubercle  bacilli 
"  immune"  to  it;  these  grew  luxuriantly  on  culture  media  with 
a  considerable  arsenic  content  and  moreover  during  their  growth 
absorbed  with  their  bodies  some  considerable  quantity  of  ?t. 
Chemical  analysis  of  these  tubercle  bacilli  has  shown  that  they 
contain  0*3  per  cent,  of  arsenic  (corresponding  to  about  o'6  per 
cent,  of  arsenious  acid).  For  a  year  we  used  the  arsenical  bacillarv 
emulsion  along  with  the  ordinary  bacillary  emulsion,  in  200 
cases  without  seeing  any  obvious  superiority  of  the  one  over  the 
other.     The  injections  are  borne  without  reaction. 


IQ4  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

New  preparations  have  been  made  by  treat- 
Molliment.  -m^  tubercie  bacilli  with  soap  and  various 

oleates.  Noguchi  [205]  has  discovered  that  soap  is  very  injurious 
to  certain  bacteria. 

With  the  idea  that  the  wax  sheaths  of  the  tubercle  bacilli  must  be  much 
better  permeated  by  soap  than  by  other  watery  agents,  he  tested  its  bacterio- 
lytic power  on  them.  He  not  only  succeeded  in  completely  killing  them, 
but  he  was  also  able  by  previous  treatment  with  tubercle  bacilli  which  had 
been  killed  with  Venetian  soap  to  immunize  guinea-pigs  against  infection 
with  a  virulent  culture  of  the  same  stock.  Independently  of  Noguchi, 
Zeuner  [206]  obtained,  by  treatment  of  cultures  of  tubercle  bacilli  with  a 
solution  of  Venetian  soap,  an  extract  containing  both  the  fatty  and  wax 
substances  and  the  protein  of  the  bacillary  bodies  which  exercises  a  distinctly 
immunizing  influence  on  tuberculosis  in  guinea-pigs. 

_  ,     __     ,  For  the   treatment   of   human   tuberculosis, 

Zeuner s  Method     r,  1*1.  *•  c  u 

Zeuner  makes  the  preparation  as  follows  : 

of  Preparation.  -r_je  extracts  and  saponifies  a  culture  of 
tubercle  bacilli  with  sodium  oleate  for  many  days  at  a  constant 
temperature  of  370  C,  shaking  the  mixture  continuously,  and 
then  heats  it  to  700  to  730  C,  so  as  completely  to  kill  all  bacilli 
and  to  break  down  the  wax-sheaths.  This  filtrate,  first  called 
"  Prosperol,"  then  "  Tebesapin,"  is  now  designated  "  Molli- 
ment  "  (Preparation  No.  8). 

Experiments    with    A»empts  to  immunize  calves,   which  tolerate  both 
1  intravenous    injections    or   the    nitrate    and    also   ot 

IVIOIIiment.  ^e   saponified  bacillary  bodies,   took  a  favourable 

course  and  promised  good  results  (Zeuner  and  Broil).  Even  guinea-pigs  50 
treated  lived  longer  than  the  control  animals.  Recent  investigations  by 
Marxer  [207]  also  show  that  sodium  oleate  can  kill  tubercle  bacilli  and  by 
the  use  of  bacillary  emulsion  treated  with  it,  immunizing  and  beneficial 
effects  on  the  course  of  the  disease  can  be  obtained  in  guinea-pigs ;  goats 
previously  treated  with  it  are  rendered  resistant  to  a  severe  artificial 
infection  or  even  completely  protected  against  it  by  suitable  experimental 
treatment. 

Citron  and  Munk  were  unable  to  promote  the  formation  of  antibodies 
by  treating  healthy  guinea-pigs  with  the  preparation ;  nor  could  they  obtain 
a  satisfactory  immunization.  But  the  average  duration  of  life  of  most  of 
the  treated  animals  was  somewhat  longer  than  that  of  the  control  animals, 
and  the  course  of  the  disease  as  regards  the  spreading  of  symptoms  was  in 
many  cases  considerably  more  favourable. 

Method    of  Use       ^n   t^e    treatment    of   human    tuberculosis,    Zeuner 

,    D         .  [208]    has    abandoned    the    original    subcutaneous 

and    KesultS.  method    on    account    of    the     painfulness    of    the 

injections.     He  administers  it  by  mouth  in  the  form  of  keratinized  pills, 

soluble  in  the  small  intestine,  and  in  hardened  gelatine  capsules  (three,  one 

to  three  times  a  day)  or  -per  rectum   (J,  \  and  1   c.c.  in  two  concentrations 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  195 

every  second  or  third  day).  Senator,  Citron  and  Masskow's  results  show 
that  the  remedy  is  well  borne.  Jessen  states  that  it  has  without  question 
an  immunizing  action.  Bergell  has  obtained  satisfactory  results,  and  the 
recent  experiences  of  the  Berlin  charities  are  also  favourable.  Weicker 
claims  good  results  even  in  severe  cases. 


.       ,  Haentjens     [209]     endeavoured    to    obtain 

J  from  the  tubercle  bacilli,  without  injury  to 

Filtrase.  ^e  Dacinary  bodies,  their  normally  secreted 

toxin    by    imitating  the     natural     processes    in     the    tubercular 

organism. 

Preparation. 


Experiments  on  animals  with  filter-candles  con- 
taining enclosed  tubercle  bacilli  show  that  the 
toxins  diffused  through  the  candles  exactly  resemble  those  which  are 
emitted  from  the  natural  tissue-wall  of  the  tubercle.  As  these  toxins  are 
also  produced  in  vitro  when  the  filter-candles  are  placed  in  a  flask  with 
distilled  water,  Haentjens  makes  use  of  the  following  procedure  to  obtain 
them.  Tubercle  bacilli  from  three  to  five  weeks  old,  grown  on  glycerine- 
potato  or  Hesse  culture  medium,  are  put  into  the  filter-candles  with  an 
equal  quantity  of  powdered  salt,  so  that  after  the  interchange  of  salt  and 
water  in  the  candles  and  flasks  normal  saline  is  produced ;  the  tubercle 
bacilli  continue  to  live  in  this,  and  are  supposed  during  their  stay  of 
fourteen  to  thirty  days  in  the  incubator  at  a  temperature  of  370  C.  to  separate 
their  toxins. 

Haentjens  describes  this  preparation,  which  he  calls  "  Fil- 
trase," as  a  genuine  endotoxin  arising  from  the  bodies  of  the 
bacilli  themselves. 


Similar    experiments    to    treat    tuberculosis 
Auto-antigens.       with  a  filtrate  obtained  from  the  patients' 

own  sputum,  which  might  be  termed  an  auto-antigen,  have  lately 
been  made  by  Ruhemann,  Passini  and  Wittgenstein,  Hoffmann 
and  Martin,  and  Roswell  Pettit,  apparently  independent  of  one 
another. 

Ruhemann,  in  particular,  claims  to  have  observed  a  favourable  influence 
of  this  sputum  filtrate  on  advanced  phthisjs.  He  has  also  used  sputum 
extract  in  other  cases — of  tuberculosis  of  the  skin,  choroid  and  bladder— 
.and  states  that  the  case  of  tuberculosis  of  the  bladder  was  thereby  cured. 

-T-   ,  .      .         .       Buchner     and     Hahn's     [210I     Tuberculo- 

Tuberculoplasmin.      ,  ..,      T,.     ,\  , 

r  plasmin  is  very  like  Koch  s  new  tuberculin. 

The  preparation   is  obtained  by  grinding  moist  tubercle  bacilli 

with    quartz    dust    and    crushing    under    high    pressure.      The 


1 96  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

investigators  obtained  good  results  in  experiments  on  animals. 
Moller  failed  to  obtain  them  in  men. 


Weleminsky  [211]  succeeded,  by  a  culture 
Tuberculomucin.  method  0f  his  owrij  in  changing  a  stock  of 
tubercle  bacilli  in  eight  years  to  such  an  extent  that  amongst 
the  products  of  metabolism,  coagulable  albumin  and  particularly 
mucin  were  produced.  The  broth,  containing  mucin  and  freed 
from  bacilli  by  filtration  through  paper  and  sterilized  by  addition 
of  phenol,  exhibited  a  considerably  greater  immunizing  power 
in  experiments  on  tubercular  rabbits  and  guinea-pigs  than 
ordinary  cultures,  and  this  increased  from  generation  to  genera- 
tion. The  active  principle  of  tuberculomucin  he  holds  to  be 
something  other  than  'the  tuberculin  doubtless  contained  in  it, 
from  which  it  differs  chemically  and  clinically.  According  to 
the  only  reports  at  present  published — those  of  Pachner  [212]- — ■ 
it  has  proved  satisfactory  in  internal  and  external  tuberculosis. 

Pachner  with  this  preparation  has  treated  thirty-five  cases  of  pulmonary 
tuberculosis  of  varying  severity  (in  unfavourable  hygienic  conditions  prac- 
tically without  subsidiary  measures)  in  ambulant  practice  with  the  result 
that  ten  were  cured,  eighteen  restored  to  working  capacity,  six  distinctly 
improved  and  able  to  work  to  a  certain  extent.  There  is  no  exact  statement 
as  to  its  influence  on  the  sputum  and  its  content  of  bacilli. 

Further,  two  cases  of  tuberculosis  of  the  skin  and  two  cases  of  caries- 
of  the  ribs  with  fistulse,  one  complicated  with  glandular  abscesses,  were 
cured ;  one  case  of  tuberculosis  of  the  iris,  ciliary  body  and  cornea  was- 
much  improved. 

_  Little    is    known    of    the    employment    and 

clinical  results  of  other  tuberculins.     These 

ere      ns.         are     chefly     unimportant     modifications    of 

Koch's  preparations  and  include  the  tuberculins  of  Hirschfelder, 

Jessen,  JVIarechal,  Jacobs,  Baudran,  and  Sciallero. 

Other  authors  have  attempted  to  prepare  an  active  and  less 
toxic  preparation  by  growing  the  tubercle  bacilli  on  other  culture- 
media  :  e.g.,  Vesely  by  growth  on  glycerine;  Maksutow  used  a 
similar  method ;  de  Schweinitz  added  phosphates  to  the  culture- 
fluid. 

The  same  object  has  prompted  experiments  in  preparing 
tuberculin  on  Koch's  principles  from  bovine  bacilli  (Carl 
Spengler),  avian  bacilli  (Roux),  blind-worm  bacilli  (Moller), 
piscine  bacilli  (Ramont  and  Ravaut),  and  from  various  acid-fast 
organisms.  No  practical  results  have  been  seen  from  these 
various    experiments. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  1 97 

<ii)  ACTIVE   METHODS   OF   IMMUNIZATION   ON   THE 
LINES  OF  JENNER  AND  PASTEUR. 

Besides  the  active  immunization  by  means  of  bacterial  cell 

substances,  an  attempt  has  many  times  been  made  to  reach  the 

same  end  with  living  and  dead  bacilli  themselves.     In  giving  a 

short  resume  of  what  has  been  done  in  this  sphere  of  work,  we 

shall   show  the   direction    in   which   previous   research   has   been 

tending  and  in  which,  to  all  appearances,  successful  inoculation 

against  tuberculosis  of  man  seems  to  lie  within  attainable  distance. 

.  .      ..  On  the  analogy  of  vaccination  in  small-pox, 

Immunization         ,  ,  ,  r  \ 

.  ,     .  ,     the  attempt  was  made  to  produce  a  form  of 

with  Attenuated     ,.   ,.  ,  ,      .   ,         ,     •      ,  r 

light    curable    tuberculosis    by    means    of 

ouitures  ,  attenuated  cultures  and  so  immunize  against 

the  more  severe  form.  The  names  need  only  be  mentioned  of 
Auclair,  Falk,  Grancher,  Masentow,  Hericourt  and  Richet,  Peron, 
Paterson  and  Tommasoli.  Following  on  Pasteur's  lines,  the 
cultures  to  be  injected  were  attenuated  by  putrefaction,  heat  or 
antiseptics ;  all  with  negative  result.  Cavagnis  recorded  favour- 
able results  of  immunization  in  guinea-pigs  and  rabbits  by 
inoculating  tuberculous  sputum,  previously  treated  with  carbolic 
acid  of  increasing  dilution.  Other  observers  obtained  satisfac- 
tory  results   by  passing  the  bacilli   through   refractory   animals. 

.....,.,       iI  De  Schweinitz  attained  a  certain  immunitv 

With  other  .  ...  ,  J 

in    guinea-pigs    by    means    ol    attenuated 

Acid-fast  Bacilli.  human  tubercle  bacilli;  similarly  Hericourt 
and  Richet  succeeded  in  man  by  means  of  avian  bacilli. 
McFadyean  [213]  produced  a  high  grade  of  immunity  in  cattle, 
both  by  injecting  the  products  of  metabolism  of  bacilli  or  their 
dead  bodies  and  also  by  injecting  living  bacilli  closely  related 
to  the  tubercle  bacillus,  specially  avian  bacilli.  Terre's  experi- 
ments with  piscine  bacilli  and  Dieudonne's  with  frogs'  bacilli 
both  gave  negative  results.  Encouraging  results  were  given  by 
Moller's  [214]  experiments  with  his  acid-fast  bacteria.  Klem- 
perer  found  in  guinea-pigs  a  checking  influence  on  the  tubercular 
infection,  but  this  was  only  temporary.  Investigation  in  the 
Institute  for  Infectious  Diseases  with  timothy,  dung,  pseudo- 
bovine  and  slow-worm  tubercle  bacilli  confirmed  this,  but  estab- 
lished only  a  delay  in  the  appearance  of  the  first  symptoms  of 
infection   and   in   the  course  of  the  disease. 

Klebs  [215]  concludes  from  his  own  experiments  on  animals 
that  the  infectious  power  of  human  tubercle  bacilli  is  much 
attenuated  by  the  antagonistic  effect  of  slow-worm  tubercle 
bacilli  and  has  used  this  antagonism  in  the  treatment  of  human 


198  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

tuberculosis.  According  to  Klebs  the  effect  is  due  to  the  trans- 
formation of  the  infectious  human  tubercle  bacilli  into  the  form 
of  slow-worm  tubercle  bacilli,  which  are  not  injurious  to  the 
warm-blooded  body.  The  slow-worm  tubercle  bacilli  are  taken 
up  by  migratory  cells  and  brought  to  the  diseased  organs. 
According  to  his  latest  communications  [216]  the  internal  method 
of  application  in  the  form  of  tabloids  with  lactose  is  quite 
satisfactory. 

Friedmann  [217]  reports  the  immunizing 
action  of  his  tortoise  bacilli  in  guinea-pigs,. 
but  the  period  of  observation  was  too  brief,  as  the  publication 
of  Libbertz  and  Ruppel  shows.  Orth  was  able  to  confirm  the 
fact  that  tortoise  tubercle  bacilli  really  belong  to  the  group  of 
tubercle  bacilli  and  produce  tuberculosis,  though  of  a  form  with 
little  tendency  to  progress ;  the  guinea-pigs  thus  treated,  how- 
ever, only  remained  alive  on  the  average  longer,  and  some  of 
them  showed  a  relatively  late  occurrence  of  typical  pulmonary 
tubercle  with  cavity  formation.  In  a  later  communication  Fried- 
mann stated  that  he  had  succeeded  in  protecting  two  cattle  by 
means  of  his  culture  against  a  subsequent  infection  with  bovine 
bacilli. 

,_  .     ,  ,  According  to  his  latest  publication,   Fried- 

Friedmann  s  r  ^on   ,  ,    ,   •  1    • 

mann   [2i8J    has  succeeded  in  rendering  a 

culture  of  tortoise  bacilli  (which  already 
possessed  but  little  power  of  causing  morbid  symptoms  and  was 
of  low  toxicity)  so  completelv  non-toxic  that  the  living  bacilli 
lost  even  the  last  traces  of  their  power  of  producing  symptoms 
and  their  toxicity,  but  still  retained  their  specific  curative  sub- 
stances. After  he  had  proved  its  value  by  many  animal  experi- 
ments and  their  harmlessness  for  man  by  trial  on  his  own  person, 
the  preparation  has  been  used  during  the  last  few  years  in  therapy 
for  tubercular  patients  of  all  kinds  in  a  large  number  of  clinics. 

D         1  Up  to  the  present  682  patients  have  been  treated, 

including  250  cases  of  pulmonary  tuberculosis,  also 
glandular,  skin,  bone,  joint,  urogenital  tuberculosis  and  scrofula.  In 
almost  all  cases  except  those  recognized  as  hopeless  from  the  start  the 
result  was  good  when  the  preparation  was  properly  absorbed.  When  it  was 
not  absorbed  abscesses  were  even  observed  and  the  preparation  was  in- 
active. By  alternate  intravenous  and  subcutaneous  injections  these  failures 
have  lately  been  avoided.  Pulmonary  tuberculosis  showed  a  regular  and 
generally  permanent  improvement,  both  subjective  and  objective;  long 
suppurating  glands  and  fistulae  were  completely  cured ;  tuberculosis  of  the 
joints  gradually  improved;  cases  of  tuberculosis  of  the  bladder  and  kidneys 
showed  distinct  improvement,  and  were  sometimes  completely  healed ;  even 
lupus  foci  of  ten  years'  standing  showed  progressive  healing  and  scrofulous 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        199 

exanthemata  of  long  duration  were  permanently  cured  without  other  methods 
of  treatment  being  applied.  After  these  conspicuously  successful  results, 
which  also  proved  the  harmlessness  of  the  method,  350  children  from  a 
tubercular  district  were  given  a  single  protective  injection  (intramuscular), 
with  the  result  that  all  thrived  splendidly,  and  since  the  injection  a  year 
ago  have  been  free  from  all  tubercular  and  scrofulous  symptoms. 

The  therapeutic  value  of  the  preparation  in  surgical  tuberculosis  was 
confirmed  in  debate  by  E.  Miiller  and  Schleich,  the  former  also  stating  its 
protective  action  in  fifty-three  sucklings.  Karfunkel  has  treated  415  cases 
of  various  forms  of  tuberculosis  in  his  Polyclinic  for  Tuberculosis.  Since 
abscess-formation  has  been  avoided  the  action  has  been  favourable  through- 
out ;  no  harm  has  ever  resulted ;  prophylactic  injections  have  shown  good 
results.  Kiister  describes  the  results  as  surprising.  P.  Heymann  also 
maintains  its  value ;  even  in  severe  forms  striking  improvement  was  often 
observed.  Blaschko  found  the  remedy  useless  for  tuberculosis  of  the  skin 
with  the  exception  of  a  very  few  cases.  Bier,  Goldscheider,  F.  Klemperer, 
Citron,  and  Konisch  are  reserved  in  their  opinion.  Wolff-Eisner  has  doubts 
concerning  the  protective  inoculation.  Schwenk  could  obtain  no  result  in 
tuberculosis  of  the  bladder  and  kidneys.  Orth,  in  his  experiments  on  animals, 
could  not  prove  any  healing  action,  but  was  only  able  to  prolong  the  life  of 
the  animal. 

The  results  obtained  with  Friedmann's  non-virulent  tortoise 
bacilli  at  all  events  call  for  continuance  of  the  experiments, 
observing  all  the  precautions  necessary  in  the  trial  of  a  new 
remedy  and  with  careful  observation,  preferably  in  a  clinical 
institute.  With  regard  to  this  protective  inoculation,  we  feel 
bound  to  call  for  the  most  extreme  caution  on  account  of  the 
doubts  raised  as  to  the  nature  of  Klimmer's  non-virulent  tubercle 
bacilli,  especially  by  Piorkowski,  who  is  inclined  to  consider  the 
so-called  "  Friedmann's  tortoise  tubercle  bacilli,"  isolated  in  1903, 
as  weakened  human  tubercle  bacilli. 

Immunization  by  oral  administration  of 
killed  cultures,  a  method  proposed  by 
Loffler  for  typhoid  protection,  is  recommended  by  Calmette  [219]. 
On  the  basis  of  his  researches  into  the  absorption  of  tubercle 
bacilli  from  the  intestine,  in  which  he  supported  v.  Behring's 
theory  of  the  intestinal  mode  of  origin,  at  the  same  time  modifying 
it  in  essential  particulars,  he  considers  that  he  has  rendered  cattle 
and  also  man  immune  by  two  doses  at  forty-five  days'  interval 
of  tubercle  bacilli  previously  killed  by  moist  or  dry  heat,  or  by 
chemicals.  Laffert,  on  the  other  hand,  was  unsuccessful  with 
guinea-pigs. 

,■%   -       .,  ,        Calmette    and    Guerin    have    recentlv    been 

Calmette  and  ,  .      ,  ,  ,  .,  / 

,  .  able,   by  growth  on  ox-bile,  to  weaken  the 

tubercle  bacilli   to  such  an   extent  that  the 

subcutaneous     infection     of     guinea-pigs     only     produced     local 


200  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

tuberculosis  and  that  the  intravenous  injection  of  ioo  mg.  into 
cattle  did  not  produce  typical  tubercles,  but  only  a  general  feverish 
loss  of  condition.  With  these  bile-weakened  bacilli,  the  authors 
produced  a  high  degree  of  immunity  in  cattle  by  means  of  an 
injection  of  25  mg.  once  a  month.  It  must  be  noted  that  the 
immune  serum  obtained  from  these  animals  did  not  display  any 
protective  or  healing  properties  in  guinea-pigs  or  cattle,  though 
in  the  latter  it  prevented  the  development  of  tubercular  foci  to  a 
certain  extent. 

v.  Behring  was  able  to  produce  in  cattle  a 

v.   Behring.  high  grade  of   immunity  to  bovine  bacilli 

by  treating  them  with  living  human  bacilli.  The  milk  of  such 
immunized  cows  he  has  recommended  as  a  preventive  against 
tuberculosis  in  infants.  Koch  and  his  co-workers  are  of  opinion 
that  "the  possibility  of  protecting  cattle  is  shown  by  v.  Behring's 
experiments,  but  that  they  do  not  indicate  any  suitable  method 
of  immunization." 

Ebeling,  Lorenz,  Roemer,  Strelinger,  and  Schricker  obtained 
successful  results.  Dammann,  after  careful  experiments  on 
animals,  could  only  attribute  slight  protection  to  the  v.  Behring 
method.  This  was  also  the  opinion  formed  by  Hutyra  and 
Eber.  After  the  researches  of  A.  Weber  and  Titze  [220]  of  the 
Imperial  Board  of  Health,  all  that  can  be  said  for  the  v.  Behring 
immunizing  process  is  that  it  increases  the  powers  of  resistance 
of  the  animal  treated  in  favourable  cases  for  about  a  year.  But 
no  practical  value  has  been  definitely  proved  to  be  possessed 
by  this  protective  inoculation. 

In  a  herd  of  cattle  which  had  been  rendered  relatively  free  from  tuber- 
culosis by  Bang's  elimination  process,  tuberculosis  spread  after  the  treat- 
ment as  quickly  among  the  cattle  protectively  inoculated  as  amongst  those 
not  inoculated.  A  final  verdict  can  only  be  based  on  the  condition  of  large 
numbers  of  slaughtered  cattle.  The  value  of  the  tuberculin  test  repeated 
every  year  is  doubtful,  because  the  tuberculin  reaction  seems  to  become  less 
reliable  owing  to  the  protective  inoculation,  and  because  the  reactivity  of  the 
inoculated  animals  in  diseased  herds  becomes  weakened  in  consequence  of 
the  frequent  opportunities  of  absorbing  bovine  bacilli. 

Vallee  [221!  achieved  no  better  results  with 
Vallee 

his  method  based  on   Behring's  principle, 

in  which  he  applied  intravenously  bacilli  obtained  from  a  horse. 

He  obtained  more  effective  protection  by  inoculating  young  cattle 

with  small  doses  of  virulent  bovine  tubercle  bacilli  or  large  doses 

of  non-virulent  bacilli  by  mouth  (c/.  Calmette).    When  animals  so 

treated  were  brought  into  close  contact  with  cattle  suffering  from 

open  tuberculosis,  they  remained  fully  protected  for  a  year ;  only 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  201 

after  two  years  did  they  show  insignificant  symptoms,  whereas 
the  control  animals  became  very  ill. 

v.  Baumgarten  [222],  by  injecting  human  bacilli  into  calves, 
produced  so  high  a  grade  of  immunity  that  they  were  protected 
against  a  bovine  infection  lethal  for  control  cattle.  Recent  re- 
search places  the  dose  for  practical  purposes  at  2  eg. 

Koch  and   his  co-workers   [223]    succeeded 
Koch,  in  producing  complete  immunity  by  means 

of  injection  of  attenuated  bovine  cultures  once  repeated.  They 
finally  worked  out  a  method  by  which  cattle  were  rendered 
certainly  immune  against  highly  virulent  bovine  bacilli  by  means 
of  a  single  intravenous  injection  of  1  to  3  eg.  of  human 
tubercle  bacilli  or  of  attenuated  bovine.  They  are  convinced  that 
this  method  of  immunization  is  intimately  bound  up  with  the 
specific  difference  of  the  bovine  and  human  tubercle  bacillus 
discovered  by  Koch. 

Tauruman's   preparation   consists  of   living 
Tauruman.  human    tubercle    bacilli    in    normal    saline. 

A.  Weber  and  Titze  [220]  tested  cattle  treated  by  Tauruman's 
method  as  to  their  power  of  resisting  tuberculosis  by  intravenous 
and  subcutaneous  injection,  by  inhalation,  by  food  and  by 
natural  infection  (stall  infection).  No  essential  difference  in  the 
immunizing  power  of  bovovaccine  and  Tauruman's  preparation 
was  seen  at  first.  Later  experiments  appeared  to  prove  the  great 
superiority  of  the  protective  inoculation,  but  this  was  to  be 
explained  by  the  elimination  of  very  important  sources  of 
infection  (necessary  slaughter  of  a  cow  suffering  from  tuber- 
culosis of  the  udder,  use  of  boiled  milk)  and  not  by  the  good 
effect  of  the  Tauruman  inoculation. 

N.B. — It  is  very  important  to  note  that  the  intravenous  injection  of 
human  tubercle  bacilli  may  give  rise  not  only  to  focal  disease  of  the  udder, 
but  also  to  localized  tuberculosis  of  the  eye  and  fungoid  disease  of  the 
joints.  In  three  cases  the  bacilli  of  the  typus  humanus  remained  2.\  years 
in  the  cattle  and  increased  without  showing  the  slightest  approach  to 
the  typus  bovinus.  The  fact  that  human  tubercle  bacilli  are  retained  in  the 
bodies  of  cattle  gave  rise  to  precautionary  measures  with  regard  to  the  sale 
of  meat  of  protectively  inoculated  cattle. 

Klemperer  [224]  established  by  experiment 
Klemperer.  Qn  cattje  ^^  immunity  may  also  be  pro- 

duced by  subcutaneous  injection  of  human  tubercle  bacilli.  In  a 
series  of  cattle  artificially  infected  with  bovine  tubercle  he  saw  a 
certain  degree  of  favourable  influence  exerted  by  subsequent  sub- 
cutaneous injection  of  human  bacilli.  Koch's  teaching  of  the 
specific  difference  of  the  two  kinds  of  bacilli  induced  Klemperer 


202  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

to  treat  tuberculosis  in  man  with  living  bovine  bacilli,  in  an 
analogous  way  to  the  active  immunization  of  cattle  with  living 
cultures  of  human  bacilli.  After  he  had  convinced  himself  of  the 
harmlessness  of  the  infection  by  experiment  on  himself,  as  Carl 
Spengler  had  also  done,  he  employed  this  method  in  cases  of 
phthisis.  Fifty-four  injections  were  given  to  six  patients.  Local 
trouble  was  slight ;  four  times  an  abscess  formed,  on  several 
occasions  a  local  thickening  remained,  in  most  the  injection  was 
absorbed  without  leaving  anything  behind.  General  disturbance 
was  never  observed ;  the  patients  even  noticed  subjective  improve- 
ment and  gained  weight.  These  experiments,  for  which  priority 
must  be  given  to  Carl  Spengler,  are  certainly  designed  to  turn 
the  scale  on  the  side  of  the  correctness  of  Koch's  teaching  of 
specific  difference. 

Roemer's  [225]  experiments  have  thrown  a 
good  deal  of  light  on  the  nature  of  human 
tuberculosis;  by  means  of  a  weak  tubercular  infection,  subcu- 
taneous or  intraperitoneal,  he  succeeded  in  protecting  guinea-pigs, 
swine  and  sheep  against  a  second  infection  with  tubercle  bacilli 
which  was  generally  fatal  for  control  animals.  He  also  further 
proved  [226]  that  this  immunity  to  reinfection  with  tubercle  bacilli 
held  not  only  with  respect  to  an  artificial  subcutaneous,  cutaneous 
or  intracutaneous  reinfection,  but  also  to  methods  of  infection 
which  either  approach  very  closely  the  natural  conditions  (food 
and  inhalation  infection)  or  directly  correspond  to  similar  natural 
conditions  (contact  infection).  He  concludes  from  this,  and  his 
conclusions  are  based  on  clinical  and  statistical  observations,  that 
also  adult  human  beings  acquire  from  outside  a  considerable  or 
perhaps  even  absolute  protection  against  fresh  infection  with 
tuberculosis  if,  as  children,  they  have  recovered  from  a  slight 
infection. 

Webb,  Gerald  Bertram  and  Williams  were  even  able  to 
inoculate  guinea-pigs  with  large  quantities  of  tubercle  bacilli 
without  producing  tuberculosis  by  making  a  first  infection  with 
an  extremely  small  number  of  bacilli  and  graduallv  increasing  it. 
After  they  had  recently  been  successful  with  this  method  in  the 
monkey  (Macacus  rhesus),  which  in  captivity  is  extremely  sus- 
ceptible to  tuberculosis,  they  have  used  it  in  small  children  of 
tubercular  parents.  The  initial  dose  was  1  tubercle  bacillus,  the 
final  dose  150.  The  children  gained  in  weight  and  main- 
tained an  unbroken  healthy  condition ;  v.  Pirquet's  test  was 
negative. 

Hevmans'  method  of  protective  inoculation 
Heymans.  .  .     .  ^,  .         ,   .       .      « 

'  consists  in  giving  the  experimental  animals 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  2O3 

little  reed  sacs  containing  dried  human  tubercle  bacilli  in  gelatine 
capsules.  There  is  no  danger  for  men  if  the  sacs  are  air-tight. 
According  to  present  investigations,  half  the  animals  died.  No 
opinion  can  as  yet  be  formed  as  to  the  protective  power  of 
Heymans'  method. 

,  Klimmer  [227]  has  published  a  method  of 

Khmmers  protective    inoculation    against   tuberculosis 

Antiphymatol.        baseci  0n  the  subcutaneous  application  of  a 
non-infective    material,    Antiphymatol,    a   method   attended    with 
good  results   for  some   years  at  the   Institute   for   the   Study   of 
Infectious  Disease  in  the  Royal  Veterinary  School  in  Dresden. 
To  prepare  the  substance,   human  tubercle 
Preparation.         bacilli    are    completely    deprived    of    their 
infecting  power  by  long  heating  to  520  to  530  (weakened  bacilli) 
or  bv  passage  through   animals   (avirulent   bacilli).        Since   the 
spring  of  1909,  only  the  second  method  has  been  used.       Anti- 
phymatol does  not  regain  its  power  of  infection  by  remaining  in 
the   animal's   body,    is    without    danger    in    use    and    does    not 
lessen  the  value  of  the  meat  and  milk  of  the  animals  inoculated. 
Out  of   seventy-one   inoculated  animals,   after  a  period   ranging 
up  to  four  years,  sixty-nine  were  found  free 
Protective  Power.    ^rQm  tuberculosis  when  slaughtered;  in  the 
two  animals  which  showed  slight  tubercular  changes,  the  previous 
tuberculin  treatment  had  not  been  carried  out  in  a  very  satisfactory 
manner.       So    that    Klimmer's    protective    inoculation    must    be 
acknowledged  as  the  best  method  known  at  present  of  protective 
inoculation  and  extirpation  of  tuberculosis  (Johne). 

.  Klimmer  also  succeeded  by  treatment  with 

Uurative  Power.  ^  non_jnfectiVe  substances  in  arresting  and 
curing  existing  tubercular  disease  in  cattle.  Out  of  seventy-four 
cattle,  introduced  to  stalls  notoriously  infected,  twenty-five  on 
inspection  of  the  flesh  after  two  to  twelve  months  proved  free 
from  tuberculosis ;  in  thirty-nine  there  was  distinct  encapsulation 
of  the  tubercular  changes  and  a  complete  absence  of  new 
processes. 

Subsequent  tests  by  Weber  and  Titze  on  protective  inoculation  showed 
that  in  four  cattle  which  had  been  treated  the  same  tubercular  changes  had 
taken  place  as  in  the  control  animals.  These  authors  state  emphatically 
that  if  the  improved  theory  of  transformation  by  passing  through  cold- 
blooded animals  be  accepted,  then  the  re-transformation  from  virulent  to 
avirulent  bacilli  in  mammals  must  be  granted  in  theory ;  but  they  consider 
them  to  be  saprophytic  acid-fast  bacteria,  as  are  often  found  in  cold-blooded 
animals. 

In  two  different  specimens  Eber  found  the  weakened  human  tubercle 
bacilli  virulent  for  guinea-pigs.     On  this  account  Weber  and  Titze  fear  that 


204  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

sufficient  certainty  as  to  their  attenuation  cannot  be  guaranteed  in  the 
manufactured  preparation  and  consider  there  is  danger  in  the  annual 
repetition  of  the  protective  inoculation  of  fully-grown  animals  giving  milk. 
It  must  be  noted  that  Klimmer  rightly  refuses  to  accept  Eber's  con- 
clusions based  only  on  experiments  on  two  guinea-pigs ;  the  resulting  cessa- 
tion of  the  use  of  the  preparation  made  from  attenuated  human  bacilli  on 
purely  technical  grounds  makes  any  discussion  as  to  its  possible  danger 
superfluous.  Doubts  as  to  the  harmlessness  of  antiphymatol  have,  however, 
been  proved  baseless  according  to  the  results  of  scientific  research  and 
practice. 

,    „         ,  Klimmer's  success  with  cattle  induced  him 

Authors  ,     ,  ,.  .,,  _,  ,. 

to  treat  the  human  subject  with  good  results. 

Experiences.  After  we  also  had  convinced  ourselves  of 
the  avirulence  of  his  preparation  by  subcutaneous,  intraperitoneal 
and  intravenous  tests  on  rabbits  and  guinea-pigs,  we  made  the 
same  experiments  as  Klimmer  to  test  the  therapeutic  value  of  his 
serum  for  tubercular  men.  From  our  experiments  we  can  only 
deduce  that  the  serum  is  borne  without  any  reaction  whatever ; 
but  we  could  not  detect  any  effect  whatever  on  the  tubercular 
process.  Klimmer  is  at  work  perfecting  his  method ;  he  con- 
siders that  hitherto  much  too  small  doses  at  too  long  intervals 
have  been  used.  We  shall  renew  our  therapeutic  experiments 
when  opportunity  occurs. 

In  connection  with  the  therapeutic  experi- 
bJartel.  ments   of   Klimmer  with  avirulent  tubercle 

bacilli,  the  experimental  work  of  Bartel  [228]  must  be  briefly 
mentioned,  the  results  of  which  seemed  to  him  important  enough 
to  serve  as  a  point  of  departure  of  a  successful  process  for  specific 
immunization  against  tuberculosis.  Bartel  discovered  that 
tubercle  bacilli  suspended  in  the  organs — especially  the  lymphatic 
tissue — of  healthy  animals  and  kept  for  some  time  in  the  incubator, 
other  micro-organisms  being  excluded,  proved  avirulent  when 
inoculated  in  the  organic  tissue  of  guinea-pigs.  After  one  or 
several  inoculations,  animals  so  treated  exhibited  considerable 
immunity  to  a  virulent  infection,  even  healing  processes  in  organs 
already  manifestly  affected  and  absence  of  any  tubercular  changes 
in  all  parts  of  the  body.  According  to  recent  researches  of  Bartel 
and  his  co-workers  Neumann  and  Leimsner,  ferments,  oleic  acid 
soaps  and  especially  lipoids  also  act  in  the  same  way  as  the 
lymphocytic  tissue  (spleen,  mesenteric  lymphatic  glands). 
Tubercle  bacilli  treated  with  these  substances  gave  rise  to  pro- 
cesses of  immunity  in  experiments  on  animals. 

Levy  used  killed  tubercle  bacilli  of  the 
Levy  s      ebean.       typus  humanus  in  making  his  new  remedy 

Tebean. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  205 

Virulent  bacilli  are  shaken  in  25  per  cent,  galactose  for  4i  days  at 
370  C.  and  concentrated  in  vacuo  until  1  grm.  of  powder  contains  5  mg.  of 
bacilli.  The  preparation,  therefore,  consists  of  whole  bacilli  killed  or  very 
much  weakened  by  galactose.  The  solutions  are  prepared  with  normal 
saline  always  immediately  before  use.  One  begins  with  1/200  mg.,  and 
gradually  increases  the  dose  at  intervals  of  two  to  seven  days,  avoiding  any 
severe  reactions,  reaching  a  maximum  of  2-4  mg.  At  the  site  of  inoculation 
small  infiltrations  are  almost  regularly  formed  which  may  last  for  weeks.  The 
formation  of  abscesses  has  also  been  observed.  Length  of  treatment  about 
three  months.     Repetition  of  treatment  should  be  made  after  a  few  months. 

Levy  and  Krencker  [229]  and  Steffen  [230]  have  reported 
good  results  in  severe  cases,  caseous-pneumonic  and  even  acute, 
florid  processes. 

(12)  NASTIN  AND  TUBERCULO-NASTIN. 

In  connection  with  the  remedies  for  producing  active 
immunization  it  remains  to  mention  the  highly  interesting 
researches  of  Deycke  and  Reschad  Bey  [231]  on  leprosy,  which 
have  had  a  certain  influence  on  the  course  of  tuberculosis  research. 
Here,  too,  the  researches  of  R.  Koch  on  his  TR  are  of  funda- 
mental importance. 

Ot^fl^+rt+Urlv  It  is  well  known  that  these  authors  obtained  a  pure 

oirepiOTnnx  ., 

culture  of  a  streptothrix,  o.  leproides,  from  a  severe 

leproides.  case    0f    leprosy.      This    organism   is    not    identical 

with  the  leprosy  bacillus,  but  with  it  they  were  able  to  attain  extensive  retro- 
gression of  the  leprous  process.  Their  researches  led  them  to  the  con- 
clusion that  the  organisms  producing  leprosy  owed  their  parasitism  prin- 
cipally to  the  fatty  substances  with  which  they  were  impregnated  and  that 
the  retrogressive  changes  associated  with  the  injection  of  living  cultures 
in  the  leprous  subject  must  stand  in  causal  relation  with  this  substance. 
It  was  therefore  their  aim  to  isolate  from  the  cultures  this  fatty  substance. 
After  much  laborious  work  they  finally  succeeded  in  producing  a  chemically 
pure  fatty  substance,  which  they  called  nastin,  and  which  proved  itself 
indubitably  the  active  agent.  The  authors  assume  that  the  true  lepra 
.,        .  bacillus  contains  a  fatty  body  identical  with  nastin 

or  standing  in  close  biological  relation  with  it, 
that  to  this  body  the  lepra  bacillus  principally  owes  its  resistance  to  the 
antibodies  in  the  organism  and  that  nastin  injections  result  in  an  active 
immunization  against  this  substance.  The  question  naturally  arose  as  to 
whether  in  the  case  of  other  acid-fast  bacteria,  especially  the  tubercle 
bacillus,  a  fatty  body  similar  to  nastin  could  not  be  found.  The  attempt 
failed  to  obtain  such  a  substance  pure,  and  they  then  studied  the  working 
of  their  nastin  in  tubercular  subjects.  On  the  day  following  the  injection 
distinct  fever  occurred,  now  and  then  of  considerable  height,  the  sputum 
often  increased  enormously  and  tubercle  bacilli,  even  when  previously 
scanty,  appeared  in  great  masses,  with  definite  evidence  of  bacteriolysis. 
In  spite  of  all  this  the  therapeutic  effect  in  general  tuberculosis  was  less 
favourable.     In  healthy  men  and  animals  nastin  is  quite  inert. 


206  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

Later,  Deycke  succeeded  in  preparing  from 
Tuberculo-nastin.  tubercle  bacilli  a  neutral  fat  analogous  to 
nastin,  which  he  called  tuberculo-nastin.  From  the  successful 
treatment  on  the  one  hand  of  tuberculosis  with  nastin,  and  on  the 
other  of  leprosy  with  tuberculo-nastin,  Deycke  deduced  the 
chemical  and  biological  identity  of  the  two  substances. 

. .        .      j_.  In  employing  nastin  in  leprosy  Deycke  observed  a 

'  certain  inconstancy  in  the  results,  which  he  attri- 

buted to  a  lack  of  leucocytes.  He,  therefore,  attempted  to  produce  a 
leucocytosis,  first  by  means  of  hetol  and  then  with  benzoyl-chloride,  a  form 
of  benzoyl  soluble  in  oil  known  in  the  trade  as  ketyn.  In  employing  this 
combination  of  nastin  with  benzoyl-chloride,  nastin-B,  the  results  in  leprosy 
became  constant  and  in  every  way  satisfactory,  even  in  cases  where  nastin 
alone  had  failed. 

Clinical  Result's  ^or  t^ie  treatment  or  tuberculosis  also  these  re- 
searches were  of  value.  Deycke  had  noted  that 
when  pure  nastin  was  employed  too  frequently  in  leprous  patients  serious 
general  disturbances,  attended  with  fever,  occurred  as  a  result  of  the 
solution  and  absorption  in  bulk  of  the  endotoxins  and  proteins  contained 
in  the  lepra  bacilli  disturbances  which  could  be  set  aside  by  ketyn.  In 
tuberculosis  also  pure  nastin  was  shown  to  be  too  dangerous  on  account  of 
its  bacteriolytic  effect  and  Deycke  employed  instead  benzoyl-nastin  in  a 
weaker  dilution. 

The  results  of  the  use  of  nastin-B  have  been  considerably 
more  promising  even  if  they  have  not  fulfilled  all  the  expectations 
of  Deycke  himself. 

Recent  Research  of  ?501?  rrecent    refarchef    of    Deycke    and 

_        ,            ,  R„      ,       Much  [232     and     233]      it     follows     that 

Deycke  and  Much.    „     ..  .-;        (  ..      ,     , 

7                                nastin  is   a   fatty   body   causing    reactions, 

common  to  certain  acid-fast  bacteria  and  further  that  treatment 

with  nastin  alone  is  useless.       On  the  other  hand,  they  obtained 

no  immunization  from  the  albumin  of  the  triturated  tubercle  bacilli 

applied  alone,  but  did  so  after  the  addition  of  nastin.     Therefore 

the  authors  considered  the  combination  of  fatty  and  albuminous 

bacillary  substances  in  the  treatment  of  tuberculosis  as  necessary 

and  full  of  promise. 

They  succeeded  with  preparations  of  lecithin,  made  partly  from  cerebral 
substance  and  partly  from  egg,  in  producing  complete  bacteriolysis  of  the 
tubercle  bacilli.  With  this  preparation,  which  contained  the  dissolved 
bodies  but  no  living  bacilli  and  which  they  called  Tb-L,  they  were  able  to 
protect  guinea-pigs  from  tubercular  infection  by  previous  treatment.  In 
the  course  of  their  researches  they  found  great  inconstancy  in  the  different 
kinds  of  lecithin  coming  from  the  same  factory,  and  it  was  proved  that  the 
bacteriolytic  power  does  not  reside  in  the  lecithin,  but  in  a  substance  as  yet 
unknown  bound  up  with  lecithin.      Only  with  difficulty   (or  not  at  all)  have 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        207 

ihey  succeeded  up  to  the  present  in  the  dissolution  of  bovine  tubercle  bacilli 
— a  noteworthy  fact  in  view  of  the  unexplained  opinions  as  to  the  specific 
differences  between  tubercle  bacilli  of  warm-blooded  animals. 

R  .   -     .     .         Deycke    and    Much    [234]     later    obtained 

.  complete  bacteriolysis  of  the  tubercle  bacilli, 

N  purine 

accompanied    by     the     dissolution     of    the 

and  Choline.        albuminous    matter    and    neutral     fat,     by 
means  of  choline  and  neurine. 

Neurine  is  specially  efficacious,  1  grm.  of  tubercle  bacilli  being  com- 
pletely dissolved  by  10  grm.  of  neurine  in  two  hours  at  560  C,  and  very 
largely  dissolved  at  2>7°  C.  Jessen,  Ditthorn,  and  Citron  have  confirmed 
this.  According  to  Ditthorn,  the  washed  bacilli  which  still  remained  un- 
dissolved in  25  per  cent,  of  neurine  after  twenty-four  hours  no  longer  grow 
nor  produce  tuberculosis  in  guinea-pigs.  Also,  no  specific  substance  can 
be  shown  to  exist  in  the  neurine  solutions  of  tubercle  bacilli  by  the  method 
of  fixation  of  complement. 

.  ,    „  1       In    the    further   course    of    their   researches 

Latest    Research     ^       ,  .'         . '  .    ,        ,.       ,     . 

Deycke  and  Much  found  that  dissolution  by 

means  of  neurine  was  too  far-reaching,  the 
Deycke  and  Much,  specific  immunizing  substances  of  the 
tubercle  bacilli  being  very  considerably  altered.  According  to 
their  latest  work,  they  have  found  almost  all  organic  acids  suitable 
which  do  not  produce  complete  dissolution  but  only  partial 
destruction  of  the  tubercle  bacilli,  so  that  their  albuminous  and 
fatty  substances  are  emulsified  in  the  fluid  and  are  still  active  as 
antigen.  With  these  products,  Much  was  able  to  produce  hyper- 
susceptibility  and  also  a  high  degree  of  immunity  in  a  normal 
animal.  Much  and  Leschke  injected  tubercle  bacilli  into  the 
peritoneum  of  guinea-pigs  previously  treated  with  it  and  claim 
that  direct  bacteriolysis  of  the  bacilli  took  place  as  in  Pfeiffer's 
experiment.  The  Deycke-Much  school  is  now  testing  the  thera- 
peutic value  of  this  bacillary  solution  and  is  hopeful  that  it  may 
finally  prove  a  remedy  of  practical  utility  in  soluble  form.  As, 
however,  the  therapeutic  action  of  these  preparations  has  proved 
very  uncertain  in  man,  Much's  aim  is  directed  to  the  production 
of  immunity  to  all  possible  "  partial  antigens  "  in  the  tubercular 
individual.  With  Citron  he  assumes  that  the  uncertain  action  of 
all  tuberculin  preparations,  including  those  made  by  the  action  of 
organic  acids  on  tubercle  bacilli,  is  due  to  the  fact  that  they  do 
not  represent  a  single  uniform  substance.  According  to  his  own 
researches  and  those  of  his  students,  the  tubercular  organism 
produces  the  particular  antibodies  for  the  bacillary  protein  and 
bacillary  fatty  bodies  in  a  varying  and  very   irregular  manner. 


208  TUBERCULIN    IN     DIAGNOSIS    AND    TREATMENT 

The  task  of  specific  treatment  must  be  to  determine  by  the  method 
of  deviation  of  complement  which  "  partial  antibodies  "  are 
present  in  insufficient  quantity  and  then  to  aid  their  formation  by 
injection  of  the  corresponding  "  partial  antigens."  In  confirma- 
tion of  these  views,  Borissjack,  Sieber  and  Metalnikow  [235] 
have  shown  by  animal  experiment  that  the  most  active  antigens 
for  the  production  of  antibodies  are  tubercle  bacillary  wax, 
bacillary  bodies  freed  from  fat,  and  lecithin,  alone  or  mixed;  and 
they  state,  too,  that  these  are  not  only  antibodies  for  the  antigens 
alone  but  also  for  living  and  dead  tubercle  bacilli. 


(b)  Preparations  Designed  to  Produce  Passive 

Immunity. 

_  Besides    the    active    method    of    producing 

immunity  so  far  considered,  the  attempt  has 
of  Keiractory        Deen  made  to  cure  tuberculosis  by  means 
Animals.  Qf  passive   immunization,    by  allowing  the 

diseased  organism  to  assimilate  ready-made  protective  bodies 
contained  in  the  blood-serum  of  animals  which  had  themselves 
been  previouslv  treated  with  tubercle  bacilli  or  their  products. 
The  most  obvious  method  consisted  in  the  employment  of  the 
blood  or  serum  of  animals  supposed  to  be  immune.  The  blood- 
serum  of  animals  artificially  immunized  by  tuberculin  injections 
was  also  tested  on  guinea-pigs.  And  a  number  of  French  authors 
report  good  results  obtained  in  this  way. 

_     .      .  Other   experiments   in    serum-therapy   were 

undertaken  by  Trudeau  and  Baldwin  with 
serum  of  immunized  asses  and  sheep, 
Serum-therapy.  as  weu  as  vvith  serum  from  fowls  and 
rabbits.  The  result  of  these  experiments  was  negative,  as  also 
was  the  case  with  Auclair's  on  the  serum  of  immunized  fowls. 
De  Schweinitz  obtained  an  immunizing  serum  by  treating  horses, 
mules  and  asses  with  the  products  of  tubercle  bacilli.  Horse 
serum  was  also  used  by  Prioleau  and  Paquin,  asses'  serum  by 
Redou  and  Chenot,  Ferran,  Dorrenberg,  Babes  and  Broca. 
These  and  many  other  experiments  in  serum-therapy  had  but  little 
result.  It  is  worthy  of  note  that  Moller  [214]  could  obtain  no 
result  with  Ferran's  serum  in  man,  and  that  in  the  case  of  guinea- 
pigs  treated  with  a  potent  goat-serum  of  his  own  a  subsequent 
infection  with  tubercle  bacilli  produced  a  more  rapid  and  fatal 
termination  than  in  the  controls.     Mention  must  be  made  of  the 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  20O, 

experiments  of  v.  Behring  on  a  tubercular  antitoxin  prepared  by 
himself.  By  gradually  increasing  doses  he  succeeded  in 
immunizing  tubercular  cattle  against  doses  of  tubercular  toxin 
fatal  to  healthy  cattle.  The  serum  of  these  animals  contains  only 
minute  quantities  of  antitoxin. 

Koch  also,  who  in  general  stands  for  active  immunization, 
tested  the  curative  action  on  man  of  sera  possessing  high  agglu- 
tinating power,  but  with  no  satisfactory  result. 

We  shall  not  describe  a  number  of  recent  attempts  to  produce 
an  active  antitubercular  serum  (Zeuner,  Lannelongue,  Bruschet- 
tini,  &c),  which  have  occasionally  given  satisfactory  results  but 
are  still  in  the  experimental  stage.  We  shall  only  discuss  the 
more  known  sera  and  the  results  obtained  with  them. 


(13)     MARAGLIANO'S    SERUM. 

_,         .  In  its  preparation  Maragliano  r2l61  was  led 

Based  on  .  ^,  „      .  -j      *■         •  a  * 

by  the  following  considerations  in  regard  to 

his  Theory  of        the  pathogenesis  and  pathology  of  tubercu- 

Immunity.  losis> 

All  the  changes  produced  in  the  body  by  tubercular  infection  proceed 
from  the  toxins  secreted  in  the  body  by  the  living  tubercle  bacilli  and 
contained  in  their  bodies.  These  toxins  or  proteins  favour  the  spread  of 
tubercle  bacilli  in  the  body.  The  body's  natural  means  of  protection,  which 
are  contained  in  the  tissues  and  body  fluids  as  well  as  in  the  blood  serum, 
possess  antitoxic,  antibacterial  and  agglutinating  powers.  These  three 
protective  properties  of  the  serum  can  be  progressively  raised  when  tuber- 
cular substances  are  assimilated  by  a  healthy  animal.  The  serum  contain- 
ing these  bodies  is  suited  for  immunization  and  for  curative  treatment  and 
stimulates  the  production  of  further  protective  bodies.  After  endless 
experiment  he  found  the  best  method  of  producing  a  serum  rich  in  anti- 
bodies to  be  the  injection  of  a  filtrate  of  young  and  virulent  tubercle 
cultures,  combined  with  a  watery  extract  of  virulent  dead  bacilli.  For  the 
treatment  of  the  animals  designed  to  provide  the  serum  he  used,  then,  both 
the  bacillary  toxins  and  their  actual  bodies. 

Animal  Horses,    cows    and    calves    proved    the    most    suit- 

able animals  and  the  injections  were  continued  for 
txpenment.  s{x  months.     The  serum  of  these  animals  protects 

guinea-pigs  and  rabbits  against  an  otherwise  lethal  infection  with  living 
tubercle  bacilli.  In  his  researches  there  was  an  increase  in  the  antibodies 
in  the  serum  of  the  animals  and  tubercular  patients  treated,  the  symptoms 
of  toxaemia  disappeared,  nutrition  improved  and  the  objective  symptoms 
of  the  tubercular  process  were  relieved.  He  estimates  that  some  20,000 
tubercular   subjects  have  been  treated   with   his   serum.     Mircoli   gives   the 

~,.    .      ,    ,-,         ,^  following    statistics  of    2,809  cases    so    treated  :    of 

Clinical   Results.       H  „    f  r    ..    ,     t  ,   •,     ■,.  0 

250  cases  of  limited  afebrile  disease,  38  per  cent. 

were  cured,  49  per  cent,  improved;  of  938  cases  of  limited  febrile  disease,  18 
14 


2IO  TUBERCULIN    IN     DIAGNOSIS     AND     TREATMENT 

per  cent,  were  cured,  54  per  cent,  improved;  of  665  cases  with  diffuse  tuber- 
cular broncho-pneumonia  without  mixed  infection,  14  per  cent,  were  cured,  43 
per  cent,  improved;  of  332  cases  with  diffuse  broncho-pneumonia  with  mixed 
infection,  9  per  cent,  were  cured,  36  per  cent,  improved;  of  712  cases  with 
cavity  formation,  6  per  cent,  were  cured,  40  per  cent,  improved ;  an  average 
of  17  per  cent,  cures  and  44'4  per  cent,  improvements.  Of  these  patients 
2,396  were  febrile;  fever  disappeared  in  1,1 11  cases,  or  46  per  cent.  In  some 
cases  the  cure  had  lasted  seven  to  nine  years. 

Maragliano  wishes  to  restrict  the  application  of  his  serum  to 

the  early  stages  of  tuberculosis.     To  the  general  question  of  the 

fight  against  tuberculosis  he  takes  up  the  position  of  prophylactic 

therapy.     His  results  from  active  immunization,   from  which  he 

expected  no  success,  may  be  passed  over  as  well  as  a  method  of 

vaccination  akin  to  Jenner's  which  he  elaborated. 

^      „.  _  Success    with    Maragliano's    serum    is    con- 

Conflictmg  ^         &  „     1       .    ~ 

firmed  by  Grotto,  Hager,  Garlucci,  Dasara, 

Evidence.  Ulrich,    de    Renzi,    Cattaneo,    Fasano    and 

others.     Mafucci  and  di  Vestea  saw  no  result ;  and  Moller  and 

Krause  nothing  appreciable.     The  result  of  two  years'  experience 

with  the  serum  in  the  Henry  Phipps'   Institute  in  Philadelphia 

seems  also  to  have  been  unfavourable,  also  the  results  of  Flick 

and  Lardis  given  at  the  International  Congress  on  Tuberculosis 

at  Washington.     Recently,  however,  the  Maragliano  school  again 

reports  successful  resuirs.       Marzagalli  and  Figari  cured  an  ape 

with  advanced  disease  and  confirmed  the  occurrence  of  scarring 

and  calcification  by  autopsy.     Cambiaso  cured  a  severe  case  of 

pulmonary  tuberculosis  by  116  injections,  which  he  was  able  to 

confirm  one  and  a  half  years  later. 

Of  his  pupils,  Livierato  proved  by  experimental  tuberculosis 
in  animals  that  the  progress  of  the  infection  was  hindered.  Added 
to  bacilli  in  vitro  it  weakened  their  virulence  and  power  of 
development.  The  blood-serum  of  tubercular  patients  showed  no 
inhibiting  influence  on  experimental  tuberculosis  in  animals,  but 
favoured  its  development:. 

Adherents  of  the  Maragliano  school — Mircoli,  Sciallero, 
Marzagalli — have  demonstrated  degenerative  changes  in  the 
tubercle  bacilli  as  a  result  of  the  action  of  antitubercular  serum, 
and  these  are  of  favourable  prognosis  for  the  individual  treated. 
Goggia  confirmed  this  in  one  case  clinically.  Ghedini  recom- 
mends, in  cases  of  tubercular  disease  of  the  joints  and  testes,  the 
-direct  local  injection  of  the  serum. 

Favourable  results  have  further  been  recorded  by  Giordano, 
Rapallo,  de  Paoli,  de  Barbieri,  Angelo,  Piola,  Chmelar  and 
Mitulescu. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  211 

(14)  MARMOREK'S  ANTI-TUBERCULAR  SERUM. 

_   .     .  ,  The  nature  of  the  tuberculin  reaction  being 

Relation  ot  r  ..  ,  .      ,         ,  . 

not  yet  fully  explained,  and  its  action  vary- 

Tuberculin  to  True   Jng  go  widely  in  the  different  stages  of  the 

Tubercle   Toxin,      disease,  Marmorek  [237]  was  led  to  take  up 

the  view  that  tuberculin  is  not  actually  the  toxin  of  the  tubercle 

bacillus,  but  that  it  stimulates  the  recipient  to  produce  another 

toxin  in  greater  quantity. 

On  his  theory  there  are  two  different  stages  of  the 

Special  Culture       tubercle   bacillus    and    different    secretory    products 

Medium    for  depending   on   the   nature   of   the  culture   medium. 

,_,   .      ...         ,-,      ....       The  production  of  the  true  tubercle  bacillus  toxin 
Primitive  Bacilli.  .    .  r  u  ,  -u       n    «     w*-      u     n-  » 

is  greatest  from  what  he  calls  "  primitive  bacilli. 

He  grows  these  on  a  medium  containing   "  leucotoxic  "  serum  and  extract 

of    liver  tissue.     In    preparing    this    complicated    medium    he    went   on    the 

assumption    that    the   presence    of   leucocytes    stimulates   the    production   of 

tubercle    toxin,    and    that    animal    experiment   has    shown    that    increase    of 

tubercle  bacilli  and  formation  of  tubercles  occur  only  with  difficulty  in  liver 

tissue.      The  presence  of  liver  extract  in  the  culture  medium  results  in  the 

bacilli  retaining  their  "  primitive  "  character  for  a  longer  time.     The  bacilli 

cultivated  in  the  primitive  stage  increase  rapidly  on  the  medium.      In  these 

primitive  cultures,  the  "  primitive  "  toxin,  the  real  tubercle  bacillus  toxin, 

differing  in    nature    from   Koch's   tuberculin,    is   formed    in    great   quantity. 

Koch's   tuberculin,    in    the   process    of  immunizing    animals,   produces    only 

anti-tuberculin    and    remains    inert    towards    other    toxins    of    the    tubercle 

bacillus;   these  latter  are  influenced  by   the  toxin   of  the   primitive  bacilli. 

With  some  30  c.c.  of  this  toxin  he  was  able  to  immunize  guinea-pigs  against 

an  otherwise  lethal  dose  of  virulent  bacilli. 

C..    .      .    _.         .,  Marmorek-  then   employed  his   serum  on  man   and 

1 1  n  1  Cf\  I     p^f1  ^  1 1  It^ 
treated     severe    cases    of     tuberculosis,     especially 

surgical   forms,    with    success.     He  recorded    the  cure    of  several    cases    of 

Pott's  disease  with  fistulse  and  abscesses  and  others  with  perforation  of  the 

intestine. 

~      a-   ,.  In  other  hands  the  remedy  has  been  very 

Conflicting  .  *  * 

variously  judged.  Dieulafoy  gave  an  un- 
favourable opinion,  obtaining  no  immunity 
in  animals  and  in  man  rather  harm  than  good,  as  also  Champion- 
niere.  Hallopeau,  in  cases  of  cutaneous  tuberculosis,  observed 
the  development  of  new  nodules  and  wearisome  suppuration  at  the 
sites  of  injection. 

Definitely  bad  results  are  recorded  by  Krokiewicz  and 
Englander ;  by  Stadelmann  in  five  cases,  and  by  Mann  in  twenty- 
three  cases  of  pulmonary  tuberculosis ;  by  Meyer  in  three  cases 
of  laryngeal  disease.  Hodesmann,  de  la  Camp,  Deneke  regard 
the  remedy  with  suspicion.  No  success  was  obtained  in  pul- 
monary   tuberculosis    by    Mackenzie,    Rubinstein,     Ganghofner, 


212  TUBERCULIN     IN     DIAGNOSIS     AND     TREATMENT 

Preleitner,  Meissen,  Szurek,  Jereslaw,  Wolman  and  M.  Elsasser. 
The  last  named  recently  [238]  showed  the  incomparably  greater 
curative  effect  of  the  bacillary  emulsion  over  Marmorek's  serum, 
the  latter  having  almost  completely  failed  in  twenty-five  cases. 

Unequal  results  are  recorded  by  Jacquerod,  Yeillard, 
Stephani.  Others,  as  Sievers,  Holmstrom,  Mannheim,  Holmboe, 
Griiner,  Strauss,  Damanski  and  Gittelmacher,  Ritter,  Kroner, 
Sokolowski  and  Dembinski,  John  Mitchell  express  themselves 
with  great  reserve.  Its  value  in  pulmonary  tuberculosis  is 
attested  by  Lewin,  v.  Rothschild  and  Brunier,  Lemieux  and 
Richer,  Veillard,  Dubard,  Latham,  Jacquerod,  Klein  and  Jacob- 
sohn,  Steinsberg,  Miiller,  Morin,  Petit,  Feldt,  Ullmann, 
Schenker,  Wohlberg,  Rover,  Uhry,  Horner,  Vos,  Germani, 
Cambiase,  Castaigne  and  Gourand,  Postnikow,  Masenti,  Roque, 
Nove-Josseraud,  Robin,  Klose.  The  best  results  were  obtained 
by  Montalti  and  even  in  advanced  cases  by  La  Neelle  and 
Cornieres,  Faraggi,  Kokler,  Levy  and  Jacobsohn.  Pfeiffer  and 
Trunk  record  entirely  satisfactory  results  in  twenty-four  cases  of 
open  tuberculosis,  some  of  them  with  laryngeal  complications. 
Roblot  saw  good  effects  in  all  afebrile  cases,  all  his  failures  being 
febrile.  On  the  other  hand,  Mongour  finds  it  valuable  just  in 
acute  febrile  cases  of  the  1st  and  2nd  but  not  the  3rd  stadium. 

C1  ..  F.    A.    Elsasser,    too    [239],    records    with 

enthusiasm  unusual  success  in  febrile  cases 
of  pulmonary  tuberculosis,  acute  and  subacute.  Most  favourable 
of  all  are  the  reports  of  surgeons  in  cases  of  surgical  tuberculosis 
(cf.  pp.  265-269). 

Much  better  results  with  the  serum  seem  to 
Y'  have  been  reached  since  it  has  been  given 

per  rectum  on  Frey's  suggestion  [240]  ;  he  has  reported  excellent 
results  on  the  basis  of  5,000  rectal  injections.  He  observed 
undoubted  specific  influence  on  the  local  tubercular  process, 
striking  reduction  of  fever  and  improvement  of  the  general  con- 
dition. 

Schenker's    observations    extend    to    sixty 

cases  of  pulmonary  tuberculosis  mostly  of 
the  2nd  and  3rd  stadium,  tuberculosis  of  the  bones,  kidney  and 
bladder  in  which  he  used  the  serum,  which  he  considers  less 
irritant  and  more  lasting,  with  good  results.  He  considers  the 
subcutaneous  method  more  certain  and  only  recommends  appli- 
cation per  rectum  when  for  some  reason  or  other  the  subcutaneous 
method  cannot  be  borne. 

,/..,  ,  Kohler   [241!   reports  very  unequal   results 

Kohler.  .         -,       7       .   {         ,-     J       ■       •   . 

in  spite  of  rectal  application  in  sixty  more 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  213 

advanced  cases.  In  twenty-two  cases  an  improvement,  sometimes 
only  a  slight  one,  was  noticeable  in  the  condition  of  the  lung,  in 
thirty-eight  cases  it  remained  unfavourable  or  was  distinctly 
worse;  scarcely  in  a  single  case  did  the  serum  treatment  lead  to 
the  removal  of  the  tubercle  bacilli  from  the  sputum.  Examination 
after  two  years  gave  a  completely  negative  result  in  forty-four 
cases,  of  which  death  occurred  in  thirty-three. 

The  good  results  of  Thorspecken  after  pro- 

Thorspecken.         longed     out-patient     treatment     were     only 

observed  in  Stadium  I  and  in  closed  tuberculosis  of  Stadium  II, 

that  is  in  cases  of  less  severity;  for  the  most  part  the  serum  was 

without  effect. 

Kaufman n  [242]  considers  the  antitoxic 
Kautmann.  substance    in    the    Marmorek    serum    to    be 

inert  on  the  tubercular  lung  process.  He  attributes  the  disagree- 
able and  harmful  symptoms  occurring  in  half  of  his  cases  to  the 
foreign  albumin  of  the  horse  serum.  The  disturbances  generally 
took  the  form  of  heart  trouble  with  high  pulse,  sometimes  con- 
siderable fever  and  interference  with  the  general  well-being,  also 
stomachic  and  intestinal  trouble.  He  also  thinks  some  cases  of 
nephritis  may  be  attributed  to  the  assimilation  of  the  foreign 
serum.  He  was  unable  to  detect  any  influence  on  the  organism 
by  means  of  Arneth's  blood  pictures. 

Turban  [243]  considers  the  serum  to  be  a 
ur   an"  specific    remedy,     beneficial     in     a     limited 

number  of  fresh  cases  of  tuberculosis  of  the  lungs  and  other 
organs,  but  does  not  immunize;  in  slight  subfebrile  cases  it  some- 
times reduces  the  fever;  in  advanced  cases  it  is  of  no  use,  and 
may,  in  his  opinion,  produce  acute  exacerbation. 

Monod  [244]  deduces  from  his  collection  of 
ono  the  literature  on  the  subject  that  the  serum 

is  both  harmless  and  effective  in  all  kinds  of  tuberculosis,  and  that 
if  applied  early  it  often  produces  a  complete  cure  in  surgical  tuber- 
culosis and  marked  improvement  in  pulmonarv  tuberculosis.  At 
the  session  of  the  Academie  de  Medecine  in  January,  1909,  he 
reported  on  ninety-three  publications  with  a  total  of  1,379 
cases  of  internal  and  surgical  tuberculosis;  65  per  cent,  of 
the  internal  cases  were  favourably  influenced,  72  per  cent,  of 
the  surgical. 

According  to  Marmorek's  last  publication 
Marmorek.  r       n        "  .      .,  .  , 

[245 J,  up  to  the  present   10,000  cases  have 

been    treated    (1,700   are    described    in    120    publications).      The 

serum  has  been  improved  by  the  addition  of  an  antistreptococcal 

component    and    a    substance    bactericidal    for    tubercle    bacilli. 


214  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

"  Hypersusceptibility  is  avoided  by  application  per  rectum. 
There  are  no  contra-indications  for  the  use  of  the  serum.  It  is 
of  great  therapeutic  value  even  in  advanced  cases ;  even  ten  cases 
of  tubercular  meningitis  have  been  cured  by  it." 

Latelv  A.  Schnoller  has  recommended  the 
Injection  into  inject'ion  of  Marmorek  serum  into  the 
Diseased  Focus,  diseased  focus ;  he  reports  the  cure  of  two 
tubercular  abscesses  and  a  good  effect  on  two  cases  of  lupus  and 
scrofuloderma.  He  also  considers  the  intrapulmonary  injection 
of  serum  in  phthisis  as  full  of  promise  on  the  ground  of  his  own 
experiments.  Jacobson  cured  two  cases  of  tuberculosis  of  the 
bladder  on  the  same  principle  by  instillation  of  the  serum  in  the 
bladder  and  attained  encouraging  results  by  direct  injection  into 
tubercular  glands,  a  tumor  albus  and  a  cold  costal  abscess. 

In     reviewing    the    experience    at    present 
Conclusion.  obtained    with    Marmorek's    serum,    one    is 

drawn  to  the  conclusion  that  a  final  verdict  with  regard  to  its 
curative  value  cannot  yet  be  given.  In  many  cases  of  fresh  and 
purely  local  tuberculosis  it  is  of  value ;  outside  this,  its  activity 
seems  to  be  limited,  especially  owing  to  the  mixed  infection  so 
often  present  in  tuberculosis. 

According  to  recent  experiments  by  Hamburger  and  Monti, 
Escherich,  Sternberg,  Breton  and  Petit,  Breton  and  Massol,  on 
the  production  of  antibodies  by  rectal  assimilation  of  antigens  and 
on  the  absorption  of  antibodies  injected  per  rectum  (tetanus  toxin, 
tetanus  antitoxin,  diphtheria  toxin,  diphtheria  serum,  cobra  anti- 
toxin), it  appears  doubtful  whether  the  antitoxins  of  Marmorek's 
serum  are  absorbed  when  thus  administered. 

(15)  HOECHST  TUBERCULAR  SERUM. 

In    spite    of    the    somewhat    discouraging 
Preparation.  reSults    of    antitoxic    serum,    the    Hoechst 

Farbwerke  have  themselves  undertaken  the  preparation  of  a  new 
serum  for  tuberculosis  on  new  principles,  of  which  full  details 
have  recently  been  given  by  Ruppel  and  Rickmann  [20].  They 
worked  on  the  assumption  that  the  methods  used  to  obtain  anti- 
toxic tubercular  sera  till  then  had  been  based  on  a  false  conception 
of  the  nature  of  tuberculin.  As  tuberculin  develops  its  toxicity 
only  in  an  organism  affected  by  tuberculosis  only  individuals 
susceptible  to  tuberculin  should  be  used  for  the  production  of  anti- 
tuberculin.  Animals  suffering  from  tuberculosis  were  not  suitable 
for  the  experiments  because  of  their  low  power  of  resistance  and 
also   because   of   the   difficulty   of   diagnosing   the   extent   of   the 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  215 

disease  and  of  limiting  its  course.  Therefore  for  the  preparation 
of  effective  tubercular  sera,  cattle,  horses  and  mules,  susceptible 
to  tuberculin,  were  treated  with  tubercle  bacilli  or  their  deriva- 
tives. The  susceptibility  was  produced  by  intravenous  injections 
of  living,  foreign  tubercle  bacilli.  In  the  blood  serum  of  the 
immunized  animals  all  known  antitoxins  appeared — agglutinins, 
precipitins,  opsonins,  bacteriotropins  and  the  specific  amboceptor 
antituberculin. 

«  c         Ruppel     and      Rickmann     summarize     the 

^^  1 1  yy\  yy\  pi  rv    nt 

characteristics  and  action  of  the  tubercular 
Properties.  serum  as  follows  ._ 

It  completely  deprives  tuberculin  and  ground  tubercle  bacilli 
of   their  toxicity   for  tubercular  animals. 

By  its  effect  on  ground  tubercle  bacilli,  non-toxic  products 
arise  which  effect  fixation  of  complement  without  the  assistance 
of  specific  amboceptors.  These  tubercle  bacilli,  saturated  with 
immune  bodies,  are  described  as  sensitized. 

Five  cubic  centimetres  of  the  tubercular  serum  have  prevented 
the  origin  of  tuberculosis  in  a  number  of  healthy  guinea-pigs 
infected  with  virulent  tubercle  bacilli. 

The  serum  appears  to  have  a  beneficial  effect  upon  tubercular 
guinea-pigs. 

It  is  well  borne  by  tubercular  men.  Experiments  to  prove 
its  therapeutic  power  have  been  successful  in  spite  of  the  diffi- 
culties met  with  in  the  treatment  of  a  chronic  disease  with  serum. 

In  order  that  the  immune  bodies  of  the  serum  may  be  used 
without  danger  in  the  treatment  of  human  tuberculosis,  the 
sensitized  tubercle  bacilli  should  be  employed  in  the  form  of  an 
emulsion  (cf.  sensitized  bacillary  emulsion,  pp.  173  to  175). 

Q   ,  ,  The   only   reports  of  its  therapeutic  action 

at   present   available   are    those    of   Sobotta 

Experience.  [246]  .    in    a    somewnat    sman    number    of 

patients  treated  with  it  he  observed  an  improvement  of  the  general 
condition,  frequent  facilitation  of  expectoration  and  especially 
a  considerable  and  often  even  astonishing  improvement  of 
appetite ;  he  did  not,  however,  observe  any  influence  on  pulmonary 
haemorrhage  or  night  sweats,  nor  any  perceptible  improvement 
•of  febrile  symptoms. 

According  to  various  unpublished  statements,  the  serum  has 
been  employed  in  varied  cases  of  tuberculosis,  both  slight  and 
severe.  Subcutaneous  injections  of  25  c.c.  are  the  rule,  repeated 
every  four  to  six  days.  If  for  any  reason  longer  pauses  must 
be  made  between  the  injections,  care  must  be  taken  to  avoid 
anaphylactic  symptoms.     This  can   best  be  done  by  giving,    in 


2l6  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

these  cases,  a  small  dose  of  o"oi  to  0^05  c.c.  on  the  same  day  as 
and  previous  to  the  regular  dose.  No  statements  of  serious 
anaphylactic  conditions  have  been  recorded ;  a  few  cases  of  serum 
exanthema  have  been  observed.  Reports  are  in  general  favour- 
able; a  small  number  of  authors  have  observed  febrile  symptoms 
after  the  injections. 

(i6)  STREPTOCOCCUS  SERA. 

A  The  fact  attested  on  all  sides  that  the  course 

of    chronic    tuberculosis    of    the     lung     is 

the  Secondary       aggravated  by   secondary   infection   due   to 

Infection.  organisms  other  than  the  tubercle  bacillus 

and  that  this  secondary  infection  makes  the  prognosis  worse  and 

the  application  of  specific  treatment  more  difficult  or  even  inert, 

has  led  to  the  preparation  of  sera  to  act  against  these  chronic 

mixed  infections.     They  were  originally  directed  not  against  the 

mixed   infections   of   pulmonary   tuberculosis,    but   against   other 

local    and    general     infections  :     staphylococcus    serum    against 

staphylococcus  infections,  especially  lymphangitis ;  pneumococcus 

serum    against    pneumonia    and    ulcus    serpens    of    the    cornea; 

streptococcus  serum  against  erysipelas,   puerperal  fever,   angina, 

phlegmons,  pyasmia,  scarlatina  and  acute  rheumatism. 

.  ,  Marmorek  r247~l>   ^'ho  made  the  first  com- 

Marmoreks  .  L  7 

prehensive    attempt    to    prepare    a    strepto- 

Monovalent  COCcus  serum,  put  forward  the  view  that  all 

berum.  varieties   of   streptococcus   in   human   infec- 

tions due  to  this  organism  are  of  one  and  the  same  species  and 
that  a  serum  must  influence  in  the  same  degree  all  varieties. 
He  raised  the  virulence  of  an  angina  streptococcus  by  passage 
through  animals,  and  with  this  culture  treated  horses  and  sheep; 
with  the  serum  of  the  latter  many  French  clinicians,-  particularly 
Marmorek  and  Bordet,  obtained  good  therapeutic  results.  Sub- 
sequent tests  made  in  Germany  (e.g.,  by  Petruschky,  Aronson, 
and  F.  Meyer)  showed  the  serum  quite  valueless.  To-day  it  has 
onlv  an  historical  interest. 

p   .        -  The    reasons    for    the    non-activity    of    the 

_  monovalent   Marmorek   serum   were   shown 

by  Denys  and  van  der  Velde  to  depend 
chiefly  upon  the  variation  in  species  of  human  streptococci.  They 
therefore  used  the  most  widely  different  strains  of  virulent  strepto- 
cocci and  thus  prepared  the  first  polyvalent  serum.  Tavel  then 
showed  that  the  raised  virulence  of  the  cultures  due  to  multiple 
passage  through   animals   is  a  drawback,    since  this   causes  the 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  21.7 

formation  of  antibodies  differing  considerably  from  those  really 
required.  In  the  preparation  of  his  polyvalent  serum,  he  there- 
fore omitted  the  passage  through  animals  and  used  streptococcus 
cultures  as   fresh   as   possible. 

Aronson  [248]  originally  took  up  Mar- 
Aronson's  Serum.  morek'.s  standpoint  that  the  streptococci  of 
man  and  animals  are  identical.  By  long  treatment  of  horses  with 
cultures  of  streptococci,  the  virulence  of  which  had  been  raised 
by  passage  through  animals,  he  obtained  a  serum  of  marked 
activity  in  animal  experiment.  Later  he  used  varying  strains 
pathological  both  for  animals  and  man. 

In  individual  cases  good  results  have  been  seen  from  this 
serum  in  streptococcus  mixed  infection  in  phthisis;  it  must  be 
used  soon  after  the  commencement  of  infection,  a  moment  difficult 
enough  to  determine. 

Menzer's  streptococcus  serum  [249]  is  pre- 
Menzer's  Serum.  parecj  ]Dy  treatment  of  horses  with  strepto- 
cocci cultivated  from  the  tonsils  of  patients  suffering  from  acute 
rheumatism.  Menzer  adopted  the  standpoint  that  a  serum  active 
for  man  must  be  prepared  from  streptococci  pathogenic  to  man 
and  intentionally  avoids  passage  through  animals.  With  this 
serum  he  has  obtained  good  results  in  chronic  streptococcal  mixed 
infection  in  cases  of  pulmonary  tuberculosis  and  Ostrovsky  has 
repeated  and  confirmed  these  results. 

The  streptococcus  serum  made  by  the 
Hoechst  Serum.  Hoechst  Far.bwerke  is  prepared  by  the 
immunization  of  horses  with  virulent  streptococcus  cultures. 
Only  human  cultures  from  the  most  varied  streptococcal  diseases 
are  employed  which  are  pathogenic  for  animals.  By  special 
culture  methods  the  pathogenicity  for  animals  is  maintained 
always  constant  and  this  without  passage  through  animals,  since 
this  produces  marked  changes  in  human  streptococcus  cultures. 
Thus  with  a  priori  virulent  original  strains  a  multivalent  strepto- 
coccus serum  is  prepared.  In  order  to  make  the  immunization 
as  effective  as  possible,  the  horses  are  first  given  a  sufficient 
"  ground  immunity  "  by  treatment  with  a  highly  virulent  strain 
passed  through  animals.  Then  each  horse  is  immunized  with  the 
original  virulent  cultures.  After  immunity  has  been  attained, 
the  sera  of  all  the  horses  are  mixed. 

Zangemeister  [250]  attributes  the  poor  effects  of  the  present 
anti-streptococcus  sera  to  the  differences  in  complement  or  arti- 
ficiallv  produced  amboceptor  or  both  in  man  and  animals.  He 
hopes  to  obtain  better  results  with  an  immune  serum  prepared 
from  the  ape,  which  he  is  now  engaged  in  making. 


2l8  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

(c)  Vaccine  Treatment. 

Vaccine  treatment,  inaugurated  by  Wright,  at  first  received 
with  enthusiasm  in  England  and  America,  has  not  received 
much  attention  in  Germany  until  lately.  This  was  due,  on  the 
one  hand,  to  the  very  difficult  technique  involved  in  the  con- 
tinuous control  of  the  opsonic  index,  on  the  other  hand  to  the 
doubt,  not  without  justification,  whether  the  value  of  the  pro- 
cedure justified  the  time  and  trouble  expended.  Lately  vaccine 
treatment  has  been  made  simpler  by  the  employment  of  a  poly- 
valent stock  vaccine  prepared   in   the   factory. 

Study  has  been  made  of  vaccine  treatment  in  tuberculosis, 
especially  of  pulmonary  tuberculosis  accompanied  by  various 
forms  of  mixed  infection,  as  to  the  nature  and  importance  of 
which  opinions  are  still  divided.  So  attempts  have  been  made 
to  render  the  body  immune  to  the  various  bacteria  which  accom- 
pany tuberculosis  by  injection  of  corresponding  vaccines.  We 
will  just  mention  a  polyvalent  streptococcus  vaccine  which 
is  on  the  market  and  Wolff-Eisner's  mixed  vaccine  made 
from  polyvalent  streptococci,  staphylococci  and  pneumococci. 
No  authoritative  statements  of  their  efficacy  have  yet  been 
published. 

(d)  Carl  Spengler's  Treatment  with  Immune 
Blood  (IK). 

_     ..  In  the  present  condition  of  inquiry  into  the 

Immune  Bodies  .         ,  .  .        ••    ,   7-        ,    ,    .  • 

question  of  immunitv,  it  is  believed  that  m 

formed   in  natural     and     artificial     immunization     the 

Bone-marrow.  specific  protective  substances  are  formed  in 
the  blood-making  organs,  chiefly  in  the  bone-marrow.  Observa- 
tions have  been  made  according  to  which  extracts  from  the  organs 
of  immunized  animals  have  proved  experimentally  more  active 
than  the  serum.  According  to  Pfeiffer  and  Marx,  the  spleen,  for 
instance,  of  animals  immune  from  cholera  is  four  times  more 
efficacious  than  the  serum  and  the  protective  'substances  appear 
in  it  when  there  is  no  trace  of  them  whatever  in  the  serum. 
Schroeder  [251]  and  his  co-workers  [252]  have  treated  tubercular 
guinea-pigs  with  the  pulped  spleen  of  vaccinated  rabbits  and 
calves  and  discovered  that  the  spleen  contains  protective  sub- 
stances against  the  tubercle  bacilli,  which  adhere  to  the  cells. 
The  whole  field  of  organotherapy  shows  how  much  was  expected 
from  this  method,  not  for  infectious  diseases  alone,  but  for  all 
branches  of  medicine.     It  is  possible  that  the  reason  no  effective 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        2  1 9 

process  of  immunization  has  yet  been  arrived  at  by  this  method 
is  that  disintegration  by  crushing,  extracting  and  pressing  is  in- 
complete. Perhaps  the  fermentation  method  lately  inaugurated 
by  Heim  has  more  hopeful  prospects  and  may  lead  to  a  perfecting 
of  sero-therapy  by  cytotherapy.  But  even  to-day  there  is  no 
certainty  as  to  which  cells  really  form  the  protective  substances 
in  the  organs;  in  general,  it  is  assumed  that  leucocytes  transport 
bacterial  products  to  the  blood-making  organs,  where  the  immune 
bodies  are  formed. 

Now   Carl    Spengler    [253]    thinks   to   have 
Principles  ot        proved  that  the  red  blood  cells  are  the  site  of 
IK  Treatment.       tjie  procjucti0n  and  collection  of  the  protec- 
tive substances  in  a  number  of  infectious  diseases  (e.g.,  leprosy, 
suppurations,   cerebrospinal  meningitis,   syphilis),   but  especially 
in  tuberculosis. 

The  real  producers  of  immunizing  substances  are,  according  to  Spengler, 
the  red  blood  corpuscles,  which,  stimulated  by  antigen  with  active  haemo- 
lysis, pass  on  their  immunizing  substances  to  the  serum,  which  alone  carries 
immune  bodies  for  consumption.  The  white  blood  corpuscles  and  the  blood 
platelets  are  centres  of  accumulation  of  the  second  order. 

The  tubercle  immune  blood  of  artificially  immunized  men  and  animals 
proved  to  its  discoverer  a  splendid  therapeutic  remedy  for  tuberculosis.  He 
calls  the  preparation  IK.  It  contains  the  immunizing  substances  chemically 
pure,  free  from  albumin  and  blood-pigments. 

It  must  be  specially  noted  here  that  up  to  the  present  it  has 
not  been  possible  to  produce  antitoxins  and  specific  immune 
bodies  in  general  free  from  albumin. 

IK   is  acid,   animal   immune   blood.      It   is 

Nature  ot  IK.  obtained  from  rabbits  which  have  been 
immunized  against  the  most  varied  human  tubercle  bacilli, 
chiefly  Bacillus  humano-longus.  The  blood  is  obtained  by 
puncture  of  a  vein  and  received  into  carbolized  saline  solution 
containing  lactic  acid  [254]. 

p  .  r  iix      According  to  Carl  Spengler,   IK  has  a  direct  anti- 

Kroperties  Ot  IK.  tQxic  and  therefore  direct  antipyretic  and  a  lytic 
bactericidal  property.  The  lytic  power  may  apparently  run  counter  to  the 
antitoxic  and  cover  it,  as  it  may  give  rise  to  reactive  fever,  when  masses 
of  virulent  bacilli  set  free  absorb  the  toxins,  but  are  not  fully  combined. 
The  lytic  action  is  also  seen  indirectly  in  the  removal  of  fever  by  decreasing 
the  vitality  of  the  bacteria. 

Treatment  with  immune  bodies  is  not  a  purely  passive  method  of  heal- 
ing, but  a  passive-active  one,  as  the  lysocidins  dissolve  the  germs  of  infec- 
tion, so  that  on  absorption  their  toxins  are  employed  for  the  active  increase 
of  immunity. 


220  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

,  Carl    Spengler    reports    results    never    yet 

"     °  obtained  with  other  methods  :   the  removal 

Keports.  Q£    fever    is    accomplished    even    in    cases 

apparently  hopeless,  and  this  in  a  surprisingly  short  time.  He 
states  that  one  of  the  most  striking  effects  is  the  rapid  diminution 
of  the  tubercle  bacilli,  which  were  often  only  occasionally  found 
after  eight  to  fourteen  days  of  treatment,  even  when  present  in 
large  numbers  at  first.  Even  the  most  severe  cases  of  phthisis 
can  be  treated  when  other  methods  offer  no  prospect  of  salvation, 
and  many  a  case  of  the  worst  type  can  be  cured. 

_      n.   _        _  Gernsheim,    Dresdner,    Rudloff,    Bergeron, 

Conflicting  Reports  ,'.,    .  '  T    i  •       c  ■ 

Brauns,    Alitulescu,    Pumr,    Lukin,    Simon, 

Peters,  Benohr,  Hoffmann  and  Willers 
other  Observers.  report  favourably  on  IK  in  cases  of  pul- 
monary tuberculosis.  Moritz  Wolff  recommends  it  for  out- 
patient treatment  of  initial  cases  in  children.  Selter  observed 
great  subjective  and  objective  improvement  in  children  with 
tuberculosis  of  the  glands  and  joints,  also  Westphal  in  febrile, 
acute  phthisis,  in  two  cases  of  tuberculosis  of  the  knee-joint  and 
one  case  of  peritoneal  tuberculosis.  Casteigno  states  that  he  has 
observed  complete  cure  of  double  tuberculosis  of  the  kidneys 
under  IK.  Apart  from  the  somewhat  fantastic  records  of  Carl 
Spengler's  co-workers,  the  remaining  favourable  reports  of  IK 
are  chiefly  from  abroad  and  therefore  uncontrollable  (Aravan- 
dinos,  Autokratoff,  Kiralyfi,  Manujloff,  Hollos,  Castaigne  and 
Gouraud,  Wollston,  Ryan,  Matson,  Griffiths,  Wein,  Wallerstein, 
Kirschenblatt,  and  the  uncritical  report  of  Herzberg  [255]). 

A  section  of  the  adherents  of  IK  seem  to  be  receding  from 
the  early  enthusiasm  which  welcomed  its  appearance.  It  is  now 
admitted  that  it  has  only  exhibited  a  really  striking  effect  in  a 
small  percentage  of  cases  treated  with  it ;  it  is  now  regarded  as 
efficacious  in  tubercular  intoxications,  improving  the  general 
condition,  allaying  night-sweats  and  reducing  subfebrile  tem- 
peratures and  regulating  the  stools. 

Weintraud,  Schaefer,  Roth,  Kerle,  Gantz,  Weihrauch, 
W.  Neumann,  Benker,  Karpilowsky,  Szaboky,  Scharl,  Starkloff, 
Breuer,  Koch,  Meissen,  Pigger,  Galecki  and  Budrynski  have  not 
recognized  any  favourable  results  in  adult  pulmonary  tubercu- 
losis, some  no  specific  action  whatsoever.  Baer,  on  the  ground 
of  his  investigations,  gives  a  decidedly  unfavourable  judgment 
of  the  remedy;  he  observed  objective  deterioration  in  the  condi- 
tion of  the  lungs  and  larynx,  decrease  in  weight,  albuminuria 
and  signs  of  intoxication.  Alexander  and  Kraft,  too,  have 
observed  changes  for  the  worse  in  the  condition  of  the  patient. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  221 

Exner  and  Lenk  state  that  it  has  no  effect  in  surgical  tuberculosis. 

Pick  has  not  been  able  to  obtain  the  slightest  action  in  cases  of 

ocular  tuberculosis. 

,   _,        ._,.       We  ourselves  have  used  IK  on  about  270 
Authors    Results  ,  .  „  , 

patients    and    especially    in    cases    01    open 

w  tuberculosis  in  Stages  II  and  III,  to  a  con- 

siderable extent  complicated  with  slighter  or  more  severe  tuber- 
cular localizations  in  other  organs,  considering  these  the  most 
suitable  test  cases. 

We  went  more  thoroughly  into  the  testing  of  IK  on  a  large 
scale  after  we  had  obtained  more  detailed  information  as  to  the 
theory  and  its  practical  application  in  Davos  on  the  invitation 
of  C.  Spengler.  This  guaranteed  the  most  absolute  uniformity 
in  our  method  of  work.  The  need  for  a  more  efficacious  remedy, 
especially  in  the  advanced  febrile  forms  of  tuberculosis,  was 
evident,  all  the  more  as  IK  was  applicable  even  in  the  most 
severe  forms  of  phthisis,  and  it  was  a  question  of  inoculating 
ready-made  immune  bodies  which  required  no  work  from  the 
organism  in  preparing  specific  protective  substances.  We  have 
given  a  detailed  account  of  our  laborious  researches  over  a  period 
of  fifteen  months  [256  and  257].  The  summary  of  our  results 
is  as  follows  :  — 

No  definite  antitoxic  effect  was  ever  noted, 
"'  either  where  there  was  slight  or  high  fever; 

nor  could  immunization  or  even  a  weakening  of  toxic  suscepti- 
bility to  tuberculin  be  proved.  As  regards  the  lytic  effect  of  IK 
we  failed  to  note  any  constant,  regular  effect  on  the  temperature, 
quantity,  bacillary  content  and  virulence  of  the  sputum.  We 
could  not  determine  a  distinct  curative  influence  of  IK  in  cases 
of  tuberculosis  of  the  lungs,  larynx,  skin,  intestine,  glands,  bones 
and  joints,  nor  a  focal  reaction  in  any  localizations  of  the  disease. 
We  worked  successively  with  eight  different  blood  solutions, 
which  represented  progressive  improvements  in  the  preparation 
of  which  some  were  intended  to  have  a  more  antitoxic  effect,  some 
a  stronger  lytic  effect.  All  these  preparations  were  equally  nega- 
tive in  their  effect.  From  our  experience,  based  on  the  most 
careful  clinical  observation  of  about  270  cases  treated  according 
to  C.  Spengler's  directions,  we  must  report  that  IK  is  absolutely 
inert  and  valueless  for  the  treatment  of  human  tuberculosis. 

,„  lj         ,  .  As  regards  the  harmful  effects  of   IK,    re- 

IK  Harmless,  but  ,&. 

ported  trom  some  quarters,  we  must  again 

assert   that  we   also   have   observed   during 

the  treatment  many  disturbances  of  general  well-being,   periods 

of  fever,   haemorrhage  and  deterioration   in  the  condition  of  the 


222  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

lungs,  but  we  did  not  consider  it  in  any  case  justifiable  to  look 
upon  the  IK  injections  as  the  cause  of  these  phenomena.  The 
above-named  phenomena  are  everyday  complications  in  the 
natural  course  of  advanced  cases  of  tuberculosis.  Among  the 
large  number  of  cases  with  which  we  have  to  deal,  such 
phenomena  must  necessarily  occur  with  a  certain  regularity  and 
conformity  to  law.  But  although  we  actually  tried  to  provoke 
a  specific  reaction  in  slight  and  in  most  severe  cases  with  the 
smallest  and  with  enormous  doses,  at  times  when  the  patient  was 
at  his  best  with  undoubted  power  to  react,  and  in  critical  periods, 
yet  IK  remained  in  every  respect  absolutely  inert. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  223 


B.— Special    Section. 


The  general  change  of  view  with  regard  to 
A  Specific  Remedy  the  value  of  the  specific  treatment  of  tuber- 
Independent  culosis  dates  from  barely  ten  years  ago  and 
of  Localization        was      chiefly      brought      about      by      lung 

specialists.  Hence  the  telling  results  are 
chiefly  in  the  province  of  pulmonary  tuberculosis.  By  slow 
degrees  specific  treatment  was  tried  for  other  tubercular  organs 
and  many  successful  results  are  recorded.  For  practical  pur- 
poses it  is  necessary  to  chronicle  these  results  separately  under 
the  respective  organs,  so  as  to  get  a  clear  idea  of  the  significance 
of  specific  treatment  in  tuberculosis  of  the  various  organs.  It 
is  obvious  that  whatever  ihe  localization  of  a  disease  process, 
if  the  same  infecting  agent  is  at  the  basis  of  it,  a  specific  remedy 
must  in  the  nature  of  things  have  the  same  curative  value, 
assuming  that  the  anatomical  changes  concerned  as  well  as  the 
function  of  the  organ  involved  and  the  acuteness  of  the 
process  allow  of  the  possibility  of  a  cure.  Now  we  shall 
see  that  the  results  with  the  various  organs  is  not  every- 
where uniformly  favourable.  Apart  from  the  actual  possibility 
of  cure  in  itself,  the  localization  of  the  process  plays  by  no  means 
a  secondary  part.  But  above  all — and  this  point  seems  to  us 
far  too  little  emphasized  in  describing  the  possibilities  of  the 
specific  treatment  of  other  organs — it  is  a  question  of  the  amount 
of  disease  in  the  lungs.  Primary  tuberculosis  of  an  organ  with 
healthy  lungs  is  seldom  seen,  the  disease  generally  proceeding 
from  the  lungs  or  their  glands ;  in  many  cases  the  pulmonary 
disease  is  not  only  the  basis  but  also  the  chief  localization  and 
determines  the  prognosis.  From  this  it  not  only  follows  that 
specific  treatment  of  all  organs  must  be  carried  out  with  constant 
consideration  of  the  pulmonary  disease,  but  also  that  the  displav 
of  its  activity  on  the  secondary  tuberculosis  of  an  organ  is  limited 
in  proportion  to  the  prominence  of  the  pulmonary  disease  and 
the  extent  and  freshness  of  the  disease  in  the  tissues.  The  larger 
mass  of  tubercular  pulmonary  tissue  absorbs  the  remedy  injected 
by  reason  of  its  avidity  in  proportion  to  the  susceptibility  of  its 
cells  to  the  toxin,   and  only  allows   it  to  act  on   the   secondary 


224  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

focus  in  a  lesser  degree  and  late.     To  know  and  recognize  this 

fact    is    necessary    both     for   correct    specific   treatment    and    for 

competent  criticism. 

A  second  point  is  also  important  :   Whatever  one's  attitude 

to  the  question  of  mode  of  infection  and  primary  disease  of  the 

organism,    the   lung   is   the   favourite   organ   for   the    ravages   of 

tuberculosis  with  which  alone  the  organism  may  be  able  to  cope, 

even   when   the   disease   is   relatively   extensive.     If   a   secondary 

focus  develops  in  another  part  of  the  body,  this  is  the  expression 

of  a  weakening  of  the  power  of  resistance  of  the  organism,  and  it 

makes  the  general  prognosis  of  the  doubly  threatened  individual 

worse.     This  fact  must  also  be  remembered  in  questions  of  the 

specific  treatment  of  secondary  tuberculosis  of  other  organs  and 

in  judging  of  its  value. 

_.       .',  .,-x       r        Now  the  question  has  arisen  whether  there 
Possibility  of  l         .  ... 

is    not    some    danger    possible    to    one    or 

another  of  the  various  organs  in  specific 
treatment.  In  the  Theoretical  Part  we  have  given  a.  detailed 
account  of  the  anatomical  healing  processes,  and  shall  again 
return  to  the  question  in  describing  the  specific  treatment  of  the 
several  organs.  Here  we  may  say  that  in  general  the  possibility 
of  destruction  of  tissue  occurring  must  be  taken  into  account. 
But  since  the  aim  of  the  modern  application  of  specific  remedies, 
as  has  been  already  set  out,  is  only  to  invigorate  and  assist  the 
natural  healing  processes,  the  danger  involved  will  not  be  other 
than  that  conditioned  by  the  natural  course  of  the  disease  in  the 
particular  organ. 

As  we  have  seen,  specific  treatment  can  be  carried  out  with 
remedies  both  for  active  and  passive  immunization.  The  latter 
stand,  both  in  efficacy  and  importance,  a  very  long  wav  behind 
the  tuberculins  intended  for  active  immunization.  Therefore  in 
describing  the  specific  treatment  of  the  several  organs,  tuberculin 
treatment  will  always  take  the  chief  place.  Where  serum  treat- 
ment has  proved  successful,  this  will  be  mentioned  at  the  con- 
clusion of  the  separate  chapters  in  cases  where  this  has  not  already 
been  done  under  the  section  on  Passive  Immunization. 

1.— PULMONARY  TUBERCULOSIS. 

All  the  experiences  which  we  have  collected  in  the  Theoretical 
Part  with  regard  to  the  principles  and  technique  of  tuberculin 
treatment  have  chiefly  been  concerned  with  our  studies  in  the 
treatment  of  pulmonary  tuberculosis.  There  remains  nothing 
further  to  be  said  on  this  head.     A  detailed  description  necessi- 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  225 

tates,  however,  a  consideration  -of  what  cases  of  pulmonary  tuber- 
culosis are  suitable  for  tuberculin  treatment. 

Koch  lays  the  greatest  stress  on  the  earliest 
Indications:         possible   application    of   the   remedy.       The 
Earliest   Possible     earjy  stage  of  phthisis  is  the  proper  object 
Application.  0f   treatment,    because   at   this  stage   tuber- 

culin exerts  its  full  and  complete  action  and,  as  he  assumes, 
can  effect  a  certain  cure.  This  warning  of  Koch's,  which  was 
entirely  forgotten  in  the  first  tuberculin  era,  was  strongly  empha- 
sized by  all  those  who  were  instrumental  in  reintroducing  the 
method.  In  the  opinion  of  certain  opponents  of  the  method  the 
limits  were  so  closely  drawn  that  only  the  most  favourable  cases 
were  so  treated  and  this  selection  entirely  explained  the  alleged 
superiority  of  tuberculin  treatment.  These  are,  of  course,  idle 
contentions  long  since  set  aside.  If  the  oldest  and  most  experi- 
enced adherents  of  the  method  insisted  over  and  over  again  on  a 
more  strict  selection  of  cases,  it  was  only  to  warn  against  the  old 
mistakes  and  avoid  a  repetition  of  the  same  mishaps  in  the  new 
therapy.  According  to  the  present-day  view,  uncomplicated 
afebrile  cases  of  pulmonary  tuberculosis  in 
Selection  of  stadiums  I  and  II  of  Turban  are  suitable 
Cases.  for  tuberculin  treatment.     The  limitation  is 

evidently  based  on  the  practice  of  the  popular  sanatoria  in  regard 
to  admission  of  cases  and  includes  the  material  in  which  working 
ability  is  likely  to  be  regained  in  the  usual  duration  of  treatment 
(three  months).  If  this  period  be  strictly  adhered  to,  then  in  point 
of  fact  the  sphere  of  action  of  tuberculin  will  have  been  nearly  ex- 
hausted. But  it  hardly  seems  correct  to  measure  the  therapeutic 
value  of  a  remedy  by  means  of  a  variable  time-period,  applicable 
only  to  a  section  of  the  population  and  dependent  on  the  momentary 
position  of  social  polity.  The  sphere  of  tuberculin  is,  in  fact,  a 
much  wider  one,  with,  of  course,  certain  natural  limits.  Tuberculin 
is  no  panacea  for  all  forms  of  tubercular  disease.  It  is  not  even 
directly  a  curative  agent  at  all  in  the  sense  that  antidiphtheritic 

T   ,  ,.  serum  is:  it  is  an  active  immunizing  agent. 

Tuberculin  an        T        ,       '  , 

In     the    first    case    the    organism    receives 

Active  Immunizing   something  ready-made  and  requires  to  make 
Agent.  no  effort  0f  its  own  ;   in  the  latter  it  must 

engender  a  reaction  due  to  the  introduction  of  the  products 
of  tubercle  bacilli,  and  this  reaction  leads  to  the  appearance  of 
protective  bodies.  In  tuberculin  treatment,  then,  the  body  has 
first  to  produce  antibodies ;  it  must  prepare  its  own  specific  pro- 
tective substances.  Labour  is  involved,  which  presupposes  a 
certain  store  of  strength.  Hence,  in  the  first  place,  all  individuals. 
15 


226  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

are  to  be  excluded  whose  vigour  is  much  reduced,  an  exclusion 
pretty  much  conterminous  with  the  forms  of  severe  mixed  infec- 
tion. Tuberculin  can  exert  no  curative  action  on  the  secondary 
purulent  processes  caused  by  the  streptococcus,  pneumococcus, 
influenza  bacillus  and  other  bacteria,  which  as  a  rule  occur  only 
in  advanced  cases  with  cavity  formation ;  there  is  rather  the  possi- 
bility that  the  unavoidable  and  severe  reactions  may  in  such  cases 
afford  opportunity  for  the  extension  of  the  secondary  infection 
and  lead  to  a  worse  condition.  But  these  are  the  only  cases  in 
which  direct  harm  can  be  caused  by  tuberculin.     According  to  F. 

.,  ,  ~  Kraus    T^sSl,    these    highlv    febrile    forms 

Kraus    Summary        .  .         L     . J    .    n  °    J       ,       . 

with  extensive  inflammation  and  subsequent 

caseation    are    not    likely    to    benefit    from 

Unfavourable  Cases.  specific     treatment.       Also     phthisis     with 

broncho-pneumonia  or  pneumonia  following  measles  or  influenza, 

extending  over  an  entire  lobe,  highly  febrile  but  without  sputum, 

•often    quickly   deteriorate   under   tuberculin    treatment.      Equallv 

unfavourable  are  those  cases  which  are  characterized  by  a  hale 

and  often   plump  appearance,   but  having  diffused  foci   in  both 

lungs ;  in  such  cases  severe  haemorrhages  and  extension  of  the 

infection  verv  often  occur  after  tuberculin.      We,   too,   stronglv 

deprecate  the  attempt  being  made  in  this  class  of  case,  which  is 

already  practicallv  hopeless. 

._    .        .  r  ..        On  the  other  hand,    the  indication  for  the 

Extension  of  the  ,      .  ,.  .  .      ,.     . 

use  ot  tuberculin  is  no  longer  to  be  limited 

n    ica  ion.  {Q    t^e    cases    eligible    for    admission    to    a 

sanatorium.  If  the  duration  of  treatment  be  prolonged  and  tuber- 
culin be  included  in  it,  the  selection  of  patients  bv  the  insurance 
companies  will  tend  to  widen  considerablv,  a  fact  which  our 
statistics  have  proved  for  years.  Emphasis  has  already  been  laid  on 
the  fact  that  a  certain  reserve  of  strength 
Limit  of  and  a  certain  degree  of  resistance  are  pre- 

Curative  Action  supposed  for  an  active  immunization. 
It  must  also  never  be  forgotten  that 
ot  uberculm.  even  with  good  training  in  diagnostic 
methods  there  are  considerable  limitations  to  our  knowledge  of 
anatomical  changes,  that  the  pathological  processes  generally 
reach  further  than  we  are  inclined  to  assume,  that  we  are  often 
dealing  with  cases  which  are  more  severe  than  we  believe  them 
to  be.  This  is  not  unimportant  when  we  come  to  judge  our 
therapeutic  measures,  and  to  assess  the  measure  of  success  possible 
and  to  estimate  the  success  attained,  especially  in  so  protean  and 
changeable  a  disease  as  pulmonary  tuberculosis.  These  considera- 
tions will  warn  us  against  overestimating  the  curative  power  of 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  227 

tuberculin,  but  will  also  help  to  prevent  an  underestimation  of 
its  value,  even  when  sometimes  the  result  of  specific  treatment 
does  not  come  up  to  our  expectations. 

Definitely  progressive  forms  of  disease  need  not  be  considered 
for  tuberculin  treatment,  nor  is  much  to  be  expected  in  the  case 
of  advanced  processes  where  much  destruction  of  lung  tissue  has 
taken  place.  Recovery  is  only  possible  within  the  range  which 
pathological  anatomy  shows  to  occur  in  the  case  of  spontaneous 
curative  processes.  It  is  therefore  advisable  to  have  a  clear  idea 
of  the  latter ;  fibrous  forms  of  the  disease,  even  when  widely 
affecting  both  lungs,  may  become  stationary,  and  through  scarring 
and  contraction  reach  a  complete  cure.  Localized  softenings  of 
even  considerable  area  may  be  cast  off  and  healing  take  place 
with  formation  of  smooth-walled  cavities  which  contract  to 
a  larger  or  smaller  extent.  Thus  even  advanced  processes 
are  capable  of  retrogressive  change  and  complete  scarring. 
Where  the  inflammatory  process  is  so  far  advanced  that  retro- 
gressive change  is  no  longer  possible,  the  disease  must 
get  the  upper  hand  with  or  without  tuberculin.  But  no  other 
tissue  of  the  human  body  is  so  fitted  for  contraction  by  cicatri- 
zation and  for  effective  healing,  after  shedding  even  of  fairly 
large  necrotic  areas,  and  for  retaining  its  functions,  as  the  lung. 
Where  masses  of  tubercles  disintegrate,  this  in  itself  admits 
the  possibility  that  in  their  further  destruction  they  may  produce 
further  damage,  as  the  tubercle  bacilli  are  not  killed.  This  will 
be  the  case  when  they  are  not  relatively  quickly  disposed  of  by 
the  natural  excretory  methods  of  the  organ  in  question.  But  for 
pulmonary  tuberculosis  these  dangers  are  not  great,  for  just  such 
an  organ  as  the  lung  is  highly  capable  of  getting  rid  of  such 
products  by  the  mechanism  of  its  natural  excretory  channels. 
Nevertheless,  there  is  need  for  great  care,  individualization  and 
very  exact  control  of  the  condition  of  the  lungs  in  the  specific 
treatment  of  the  more  advanced  stages,  where  such  dangers  are 
greater  than  in  slight  infiltrations  and  smaller  disseminated  foci. 

.  The    value    of    a    therapeutic    agent    is    not 

Improvement  .       . 

exhausted  with  its  absolute  curative  power. 
where  Recovery     Hammer  r^.^  has  laid  stress  on  this  point 

is  Impossible.  with  convincing  clearness.  If  in  the  more 
severe  and  in  the  worst  forms  of  pulmonary  'tuberculosis  complete 
recovery  is  in  the  nature  of  things  unattainable,  improvement  may 
yet  be  reached,  and  tuberculin  has  its  place  in  the  front  rank  of 
remedies  for  treating  special  symptoms.  Dry  cough  disappears 
or  loses  its  distressing  character;  sticky  sputum,  difficult  to  bring 
up,  becomes  more  fluid  and  expectoration  more  easy;  the  painful 


228  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

effort  to  bring  up  something  by  prolonged  coughing  ceases,  as 
well  as  the  associated  vomiting,  the  patient  regaining  his  peace 
and  quiet ;  pleuritic  pains  are  favourably  affected  by  the  greater 
ease  of  expectoration  and  the  lessening  of  cough,  also,  more 
directly,  symptoms  such  as  headache,  palpitation,  dyspnoea,  fever 
and  night-sweats  may  be  got  rid  of  for  a  longer  or  shorter  time ; 
the  appetite  improves,  tiredness  and  weakness  vanish,  bodily 
strength  returns  to  some  extent;  at  the  same  time  the  spirits 
improve,  hope  of  recovery  awakens,  and  the  will  to  persevere  in 
the  treatment  is  strengthened.  Since  the  mind  reacts  on  the  body, 
all  these  are  factors  of  immeasurable  importance  in  a  disease  of 
such  chronicity  and  presenting  such  difficulties  for  the  physician. 
The  impression  is  unmistakable  that  the  tuberculin-treated  patients 
improved  greatly  in  appearance,  and  that  even  in  the  severe  and 
incurable  cases  the  resistance  of  the  body  can  be  markedly  raised. 
Such  subjective  improvement,  which  may  be  accompanied  also  by 
amelioration  of  svmptoms,  speaks  loudest  for  the  value  of  tuber- 
culin when  it  is  reached  in  out-patient  practice  in  the  absence  of 
drug-treatment  and  under  unfavourable  conditions  of  life. 

A    h        ,  Based  on  our  own  experience,  we  should  say 

Authors 

that,  setting  aside  the  severe  incurable  forms 

Conclusions.  r  •   n  r 

of   consumption,    especiallv  cases  of   severe 

mixed  infection  with  pyrexia,  everv  uncomplicated  case  of  pul- 
monary tuberculosis  may  be  submitted  to  the  mild  method  of 
tuberculin  injection,  avoiding  as  far  as  possible  all  reaction. 

Other  observers  have  drawn  up  a  list  of  contra-indications  to 
the  use  of  tuberculin  in  treatment,  to  which,  in  view  of  their 
importance  in  practice,  we  must  now  turn  our  attention. 

C_    .       ...      ..  Under  the  term  "  fever  "  two  different  con- 

ontra-mdications  :    ,.  .  ..    .        .  ,     .  . 

ditions  are  to  be  distinguished  :  that  due  to 

the  settling  of  the  streptococcus,  pneumo- 
coccus,  staphylococcus,  influenza  bacillus,  or  other  bacterium  in 
the  diseased  area,  a  condition  known  as  mixed  infection — secon- 
dary suppurative  processes ;  and  the  pure  toxic  fever  due  to 
absorption  of  the  toxins  of  the  tubercle  bacilli.  The  latter  is  by 
no  means  unsuited  to  tuberculin  treatment.  But  even  the  mixed 
infections,  on  which  tuberculin  can  exert  no  direct  action,  do  not 
begin  fully  developed ;  with  favourably  situated  and  curable  tuber- 
cular lesions  the  tuberculin  exerts  an  indirect  action  on  the  fever, 
as  the  curative  process  renders  the  growth  of  the  secondary  bacteria 
more  difficult  and  the  culture  medium  on  which  they  flourish  is 
withdrawn.  There  need  only  be  special  care  in  giving  the  injec- 
tions to  employ  minute  doses,  to  let  the  rise  of  temperature,  which 
generally  occurs,  completely  fall  to  normal  before  repeating  the  in- 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  229 

jection,  and  when  necessary  to  reduce  the  dose  and  increase  the 
interval.  If  the  fever  is  increased  by  the  repetition  of  the  same 
dose,  this  must  be  reduced  after  a  longer  interval.  If  no  advance  is 
made  by  the  repetition  of  small  doses,  a  severe  reaction  with  an 
increased  dose  may  be  the  beginning  of  a  permanent  fall  of  tem- 
perature. The  fall  of  temperature  is  very  seldom  acute.  The 
temperature  usually  rises  at  first  quite  or  nearly  to  its  original 
height  and  only  after  repetition  several  times  definitely  begins 
to  fall;  in  view  of  the  severe  reactions,  the  intervals  should  be 
increased  to  eight  to  ten  days.  This  effect  in  reducing  fever  we 
have  noticed  more  with  the  bacillary  preparations,  especially 
bacillary  emulsion,  than  with  old  tuberculin  preparations.  From 
other  quarters,  too,  tuberculin  has  often  been  recommended  as 
a  means  of  reducing  fever,  for  example  by  Aufrecht,  Denys, 
M.  Elsasser,  Gabrilowitsch,  John,  F.  Krause,  Philippi,  Sahli, 
Schroder,  C.  Spengler,  Turban.  Which  preparation  is  the 
most  effective  in  reducing  fever  is  a  matter  on  which  opinions  are 
divided.  Small  and  very  small  doses  are  usual  in  seeking  to 
reduce  fever.  As  in  many  other  difficult  situations,  definite 
directions  cannot  here  be  given.  The  treatment  of  fever  is  most 
emphatically  individual ;  the  principle  can  only  be  stated  or 
illustrated  by  an  example.  Personal  study  is  necessary  for  the 
beginner  and  tuberculin  treatment  should  first  be  tried  on  the 
slighter  uncomplicated  case,  with  good  resisting  power,  before 
coming  to  the  more  severe  and  febrile  forms,  which  often  demand 
great  patience  both  on  the  part  of  doctor  and  patient.  Care 
must  be  again  enjoined  and  the  point  emphasized  that  in  tuber- 
culin treatment  nothing  is  gained  by  violence.  The  period  of 
treatment  may  be  lengthened  by  waiting,  but  no  harm  results. 
Employment  of  too  large  or  too  frequent  doses  leads  to  over- 
loading with  toxin,  and  this  applies  also  to  the  treatment  of 
pyrexia.  We  would  just  like  to  point  out  that  the  treatment  of 
fever  tested  by  us  is  in  every  detail  the  same  as  the  final  method 
of  R.  Koch,  as  may  be  seen  from  the  publications  of  Jochmann 
[171]  of  the  Rudolf  Virchow  Hospital. 

We  have  been  able  definitely  to  reduce  fever  in  the  slight  and 
intermediate  grades  in  Stadium  I  and  II  by  sufficiently  prolonged 
treatment,  in  Stadium  III  only  in  the  cases  of  more  favourable 
prognosis  in  which  the  patients  were  able  to  return  to  work. 

Chart  20  shows  rapid  loss  of  fever  in  a  severe  case  of  sub- 
acute caseous  phthisis,  with  high  to  moderate  fever  of  four 
months'  duration. 

Chart  21  is  an  example  of  gradual  loss  of  fever  in  a  chronic 
case    of   fibroid    phthisis     with     slight    febrile    symptoms.     Both 


23O  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

cases  were  treated  with  bacillary  emulsion,  the  doses  being  at 
first  small,  but  increased  each  time  by  one  half  of  the  preceding 
dose,   without  frequent  or  severe  reactions  taking  place. 

Chart  23  shows  a  more  gradual  loss  of  fever  in  a  case  of 
tuberculosis  of  the  bronchial  glands,  with  slight  pulmonary 
tuberculosis,  rapidly  rising  doses  of  sensibilized  bacillary  emul- 
sion being  used.  This  patient  was  never  confined  to  bed  during 
the  fever.  We  have  found  that  cases  with  obstinate  slight  fever 
treated  by  tuberculin  can  be  allowed  out  of  bed  much  sooner 
than  those  not  treated  specifically,  without  increasing  the  fever 
or  lowering  the  general  condition  in  any  way.  Of  course,  careful 
observation  and  regular  control  of  the  body-weight  are  essential. 
Debilitv  is  also  no  absolute  bar  to  tuberculin 

'    >  y  '        treatment.    The  body,  if  its  strength  is  much 

reduced,  is  not,  it  is  true,  capable  of  responding  to  the  part 
assigned  to  it  in  the  injection  of  tuberculin,  the  formation  of  anti- 
bodies. It  is  then  generally  a  question  of  widespread  tubercular 
changes.  Where  this  is  not  the  case  and  the  specific  changes 
offer  prospect  of  recovery,  then  a  bad  condition  of  nutrition,  great 
anaemia  or  general  weakness  is  only  a  ground  for  double  care  in 
the  employment  of  tuberculin.  If,  however,  there  is  time  to  wait, 
it  is  highly  advisable  before  beginning  tuberculin  treatment  to 
improve  the  constitution  by  other  therapeutic  means,  hyper- 
alimentation, improvement  of  the  blood,  &c.  We  have  often  been 
unable  to  wait  and  have  begun  at  once  with  careful  injections, 
employing  at  the  same  time  all  other  therapeutic  means  as  adju- 
vants. In  so  doing  we  have  never  had  to  suspend  the  injections 
on  account  of  low  vitality.  Preciselv  under  the  influence  of  tuber- 
culin the  constitution  obviously  improved,  appetite  became  better, 
weight  increased,  pulse  slower  and  fuller,  feeling  of  well-being 
and  bodily  vigour  returned,  and  the  composition  of  the  blood 
became  better  to  the  naked  eye.  In  any  case  tuberculin  treatment 
is  not  excluded  by  a  general  condition  of  debility,  poor  nutrition, 
lack  of  appetite,  dyspepsia  from  various  causes,  and  the  severer 
kind  of  anaemia,  but  a  careful  trial  is  permissible  and  generally 
successful.  According  to  F.  Kraus,  even  the  so-called  cachectic 
tuberculosis,  with  unfavourable  general  condition  and  appearance, 
often  with  but  slight  pulmonarv  signs,  is  extremelv  favourable 
for  tuberculin  treatment. 

j-rr-  r  Recent  blood  examinations  are  such  as  to 

Effect  of  ... 

_  ,  ,  ,        strengthen  reliance  on  treatment  with  tuber- 

Tuberculin  on  the    ^,,1-       ,1     1  ,  -,  •  ,     .     r  .1      ,  ,      , 

culm  ;  the  haemoglobin  content  01  the  blocd 

Blood.  rises,    red   and   white   blood  corpuscles    in- 

crease in  number,  and,  according  to  Arneth,   hand  in  hand  with 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  .23 1 

the  increased  dose  of  tuberculin  goes  an  improvement  of  the 
neutrophile  blood-picture,  far  greater  than  occurred  in  a  parallel 
series  of  cases  treated  by  other  methods  (Uhl,  Deneke,  Catoir, 
v.  Bonsdorff,  Franke).  According  to  Bischoff,  Botkin,  Rille, 
and  others,  injections  of  tuberculin  produce  more  or  less  definite 
leucocvtosis  and  increase  of  the  eosinophile  cells,  which  Teich- 
muller  considers  to  be  of  favourable  prognosis.  The  careful  and 
valuable  work  of  Maryan  Franke  [260]  deserves  special  considera- 
tion. He  succeeded  by  prolonged  injections  of  tuberculin  of 
human  origin  into  guinea-pigs  and  dogs  in  producing  (1)  an 
increase  in  the  red  blood  corpuscles,  and  discovered  the  cause 
of  this  to  lie  in  an  increased  production  of  these  corpuscles  in 
the  erythroblastic  tissue  of  the  blood-forming  organs,  and  (2)  in 
establishing  a  polynuclear  neutrophile  hyperleucocytosis,  espe- 
cially as  the  result  of  a  proliferation  of  the  myeloid  portion  of 
the  bone-marrow.  According  to  his  investigations,  bovine  tuber- 
culin produces  in  the  same  animals  a  direct  destructive  effect  on 
the  red  blood  corpuscles  and  the  granulated  leucocytes  in  the 
bone-marrow,  with  increase  of  the  lymphocytes  and  the  simul- 
taneous appearance  of  slight  metaplasia  of  the  bone-marrow.  It 
would  be  valuable  to  know  the  results  of  these  experiments  on 
human  beings,  both  as  regards  diagnosis  and  therapeutics ;  un- 
fortunately very  little  has  been  done  in  this  direction,  and  what 
little  has  been   done   is   of   no   importance. 

,_,  _       .  Tendency  to  haemorrhage  we  do  not  regard 

(3)  Tendency  to     .         ■     ■"  ,  ,  ."1  ,• 

'  in  principle  as  a  bar  to  tuberculin  treatment, 

Haemorrhage  ;  nQr  as  an  judication  to  stop  it  altogether. 
In  cases,  of  slight  haemorrhage  the  injections  can  be  continued 
without  interruption.  A  considerable  haemorrhage  should,  of 
course,  be  the  occasion  of  a  pause  in  the  injections  and  of  special 
care  in  increasing  the  dosage,  so  as  not  to  run  the  risk  of  a  re- 
action at  this  time.  But  it  has  never  happened  in  our  experience 
that  a  haemoptysis  during  tuberculin  treatment  has,  on  persisting 
with  the  injections,  recurred  in  such  as  way  as  to  justify  the  deduc- 
tion of  a  causal  relation  between  them. 

Moreover,  relapses  are  of  frequent  occurrence  in  haemorrhage 
of  the  lungs ;  yet  although  the  number  of  our  tuberculin  patients 
who  have  suffered  from  previous  haemorrhage  is  high,  relapses, 
in  spite  of  the  employment  of  the  largest  doses  of  tuberculin,  are 
most  rare.  And  since  our  total  number  of  tuberculin  patients 
has  been  large  and  it  has  been  rather  the  severer  cases  that  have 
been  chosen  for  treatment,  the  rarity  of  haemoptysis  is  in  favour 
of  the  view  that  tuberculin  does  not  increase  the  liability  to  it. 
To   the   rare   exceptions   may  belong  the   breaking    down     of    a 


232  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

tubercle  in  the  wall  of  a  blood-vessel  caused  by  the  local  reaction 
when  the  tubercle  lies  in  the  immediate  neighbourhood  of  a  cavity. 
But  when,  in  the  neighbourhood  of  a  blood-vessel,  a  focus  which 
is  already  bound  to  break  down  is  softened  by  tuberculin,  render- 
ing possible  the  occurrence  of  an  aneurysm  and  a  rupture,  this 
is  merely  part  of  the  natural  course  of  the  local  diseased  process, 
which  would  have  taken  place  in  the  same  way  if  tuberculin  had 
not  been  used.  This  is  also  the  view  of  those  with  the  widest 
experience  in  the  treatment  of  tuberculosis  and  has  recently  been 
confirmed  by  numerous  sanatorium  reports  and  papers  read 
before  congresses,  which  confirm  the  harmlessness  of  tuberculin 
in  haemoptysis.  By  some  tuberculin  is  even  regarded  as  an  agent 
for  preventing  haemoptysis,  the  view  evidently  being  that  the  local 
hyperemia  caused  by  the  local  reaction  distributed  over  the 
diseased  area  draws  the  blood  away  from  the  ruptured  vessel. 
Perhaps  also  the  saturation  of  the  hyperaemic  tissue  leads  to  a 
compression  of  the  rent  in  the  vessel  and  to  better  thrombus- 
formation.  Grau's  [261]  experiments,  too,  are  interesting  and 
valuable,  proving  the  increase  in  the  coagulability  of  the  blood 
after  injections  of  tuberculin,  which  he  explains  as  the  result 
of  the  reaction  of  the  organism  to  the  introduction  of  foreign 
albumin.  Thorner  observed  the  tendency  to  haemorrhage  dis- 
appear under  tuberculin  treatment,  Lowenstein  and  Kauffmann 
continued  the  injections  in  a  great  number  of  cases  of  recurring 
haemorrhage  and  never  noticed  any  harmful  effect.  Th.  Cursch- 
mann  has  never  seen  frequent  haemorrhages  during  tuberculin 
treatment;  on  the  contrary,  patients  who  had  previously  often 
suffered  from  them  were  only  exceptionally  troubled  by  haemo- 
ptyses  during  treatment.  A.  Schnoeller  even  considers  habitual 
sufferers  from  haemophilia  good  subjects  for  treatment  with 
tuberculin.  Kraemer's  experiences  go  to  show  that  patients 
treated  with  tuberculin  are  generally  protected  from  the  occur- 
rence or  repetition  of  haemorrhage. 

/a.\  mi     u       n  Abnormal  conditions  of  the  heart  can  only 

'  "be  regarded  as  a  contra-indication  to  treat- 

ment with  tuberculin  when  febrile  reaction  and  toxic  absorption 
cause  a  risk  of  disturbance  of  compensation  and  collapse.  The 
danger  may  be  met  by  the  timely  exhibition  of  powerful  heart 
tonics,  but  loses  its  importance  when  the  method  of  treatment 
is  the  mild  one  avoiding  reactions.  Valvular  lesions  are  not 
common  in  the  subjects  of  pulmonary  tuberculosis.  Lesions 
impeding  the  circulation  through  the  lung  make  the  occurrence 
of  pulmonary  tuberculosis  more  difficult  or  exclude  it  altogether; 
cases  of  existing  pulmonary  tuberculosis  with  accidental  valvular 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  2T,3 

lesions  have  a  bad  prognosis  and  are  unsuitable  for  tuberculin 

treatment;  well-compensated  lesions  are  no  bar  to  the  treatment. 

Degenerative  processes  in  the  heart-muscle  and  coronary  vessels, 

as  well  as  severe  functional  affections  of  the  heart,  demand  great 

caution  in  the  application  of  the  method  or  giving  it  up  altogether ; 

numerically  they  are  quite  insignificant.      In   principle  they  are 

n  .     contra-indicated  to  the  same  extent  as  other 

r^aniC  severe    organic    diseases,     such    as    severe 

Diseases.  diabetes,  many  forms  of  nephritis,  cirrhosis 

of  the  liver,  &c,   in  which  the  prognosis  is  already  bad.     The 

mere  presence  of  albumin  in  the  urine,   however,   is  in  itself  no 

contra-indication ;   each  case  must  be  considered    on     its    merits 

and    a    careful    test    made    where    there    is 

Albuminuria.         doubt.     We  have  some  experience  of  cases 

in    which    the   passing   of   albumin    and    renal    epithelium    ceased 

under    tuberculin    treatment,    but    where    the    diagnosis    of    renal 

tuberculosis  was  by  no  means  certain. 

Peters  (Davos)  informs  us  that  he  holds  neither  chronic  nephritis  nor 
even  diabetes  to  be  a  contra-indication  ;  he  has  never  had  to  suspend  tuber- 
culin treatment  on  account  of  these  complications.  In  one  case  in  which 
diabetes  had  existed  for  years  with  7  per  cent,  of  sugar  in  the  urine  in  a 
patient  with  severe  phthisis,  the  sugar  completely  disappeared. 

,_,  _         .        ,        Finally,  among  the  contra-indications  have 

(o)  Functional        ,  J        .        ,  ,  .  .,,    .. 

v   '  .  been   mentioned  hysteria,   with  its  varieties 

Nervous  Disease.    Q^    neura.sthenia   and    the   severer    forms   of 

il  nervousness,"  as  well  as  epilepsy.     With  equally  good  reason 

all     other     functional     neuroses — neuralgia,     migraine,     habitual 

headache,  and  the  like — might  have  been  included.     On  the  basis 

of  our  own   experience  we  can   definitely   state  that  there   is   no 

justification  for  this  exclusion  except  in   the  case  of  the  severer 

forms,  when  the  hindrance  is  more  on  external  grounds.     There 

seems   to    us    no    logical    reason    for    making   the    exclusion.      A 

sanatorium  for  tubercular  women  affords  material  enough  of  this 

kind,  and  no  special  difficulties  due  to  these  complications  have 

arisen,  except  those  inherent  to  the  conditions  themselves.     We 

may  quote  two  cases  of  well-marked  Graves'  disease,    in   which 

not  onlv  the  usual  heart  disturbances  were  present,  but  a  number 

of    other    nervous    symptoms    (giddiness,   headache,   excitability, 

hysterical   symptoms,    tremor,   affection    of   the   sympathetic,   and 

alteration  of  the  secretions) ;  in  both  of  these  tuberculin  treatment 

could  be  carried   to  a  successful   finish   with   good   influence  on 

both  diseases.     Kraus  also  does  not  consider  Graves'  disease  a 

contra-indication. 


234  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

_  ,  ...  There    is    only    to    add    that,    in    common 

Tuberculin   in  .      ~  '  D  ,  ,       c  , 

with  Denys,  Hammer,  Petruschky,  Scherer, 

Pregnancy.  Kalabin,    and    others,    we    have    treated    a 

considerable  number  of  pregnant  women  with  tuberculin ;  this  is 
always  well  borne,  with  excellent  results.  In  no  case  was 
pregnancy  a  drawback  to  the  use  of  tuberculin.  In  this  con- 
nection we  may  also  mention  that  therapeutic  tuberculin  injections 
need  not  generally  be  suspended  during  menstruation,  but  that 
pre-,  inter-,  and  post-menstrual  rises  of  temperature  must  be 
noticed  and  recognized.  Any  increased  tendency  to  reaction  (as 
shown  by  v.  Dungern,  Hirschfeld,  and  Schenk  to  occur  in  animals) 
to  certain  subcutaneous  injections,  and  which  may  also  possibly 
be  feared  for  tuberculin,  we  have  never  observed.  On  the  con- 
trary, Stern  has  just  proved  that  the  degree  of  reaction  to  the 
cutaneous  test  decreases  towards  the  end  of  pregnancy.  If,  as 
Stern  assumes,  this  phenomenon  is  due  to  a  decrease  of  antibodies, 
which  possibly  explains  the  unfavourable  influence  of  pregnancy 
on  the  disease,  then  tuberculin  treatment  is  definitely  indicated 
in  pregnancy.  The  fear  that  a  tuberculin  reaction  may  cause 
abortion  is  groundless  when  the  sexual  organs  are  sound  and  the 
foetus  healthy.  Hammer  and  Petruschky  even  state  that  children 
born  after  a  course  of  tuberculin  were  particularly  strong  and 
healthy,  and  also  grew  up  so. 

We  have  now  alluded  to  the  last  ground  sometimes  given 
as  an  objection  to  tuberculin  treatment  and  have,  in  so  doing, 
limited  to  their  necessary  minimum  the  contra-indications  in 
general.  These  the  beginner  will  have  to  construe  more  widely 
and  stringently  than  the  practised  clinician,  a  fact  on  which 
emphasis  has  already  been  laid. 

2,— TUBERCULOSIS  OF   THE   RESPIRATORY  TRACT. 

m^o^  ^„a  Tuberculin  has  been  strongly  recommended 

..  .  in     tuberculosis     of    the     nose    and     naso- 

Naso-pharynx.  ,  ,  ,         ~       ,.       ~  ■  •    ■    , 

r       '  pharynx     (e.g.,      by     Onodi,      Rosenberg, 

Schnitzler).  Also  lupus  of  the  pituitary  mucous  membrane  has 
been  successfully  treated  with  tuberculin  by  various  authors. 
According  to  Wichmann,  tuberculin  alone  has  proved  successful 
in  the  latter  disease  and  deserves  to  be  used  in  all  suitable  cases. 
In  extensive  infiltrations  and  tumours,  especially  in  the  cartila- 
ginous nasal  septum,  operative  measures  must  aid  and  prepare 
for  specific  treatment.  The  real  domain  of  tuberculin,  both  in 
the  nose  as  in  the  upper  respiratory  passages  in  general,  is  in 
ulcerative  processes.     As  Blumenfeld  [262]   clearly  explains,,  the 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  235 

conditions  for  the  healing  action  of  tuberculin  are  specially 
favourable,  as  the  necrotic  parts  of  the  tissue  can  be  shed  from 
the  free  surface.  As  for  choice  of  cases  and  technique,  with 
regard  to  the  fact  that  pulmonary  tuberculosis  is  generally  present 
as  a  primary  disease,  the  following  description  of  the  specific 
treatment  of  laryngeal  tuberculosis. will  apply. 

Wherever  the   task   of  treating  pulmonary 

Pulmonary   Disease    tuberculosis    is    undertaken,    no    matter    on 

underlying  what  lines,   disease  of  the  larynx  demands 

Tuberculosis  of       and    receives    careful    attention.     But    one 

Larvnx  nas    ^e    impression     that    in    the    special 

treatment  of  laryngeal  affections,  that  of  the 
underlying  pulmonary  disease  is  often  overlooked.  And  this  is 
the  more  striking  since  tuberculosis  of  the  larynx -is  only  seldom 
primary,  and  in  the  vast  majority  of  cases  accompanied  by  an 
affection  of  the  lung  from  which  it  has  originated.  It  is  not  our 
object  to  go  into  the  causes  of  this  phenomenon  ;  we  only  desire 
to  point  out  that  tuberculin  is  a  means  of  filling"  up  this  patent 
gap.  Not  merely  is  it  a  rational  proceeding  to  treat  a  complica- 
tion of  similar  origin  to  the  disease  on  the  same  principles  as 
the  disease  itself,  but  a  course  of  tuberculin  will  often  limit  the 
local  treatment  of  the  laryngeal  disease. 

The  method  of  treatment  is  the  same  as  for  pulmonary 
disease  and  is,  as  a  rule,  subservient  to  the  treatment  of  the 
latter.     Selection   of  cases   is   therefore   conditioned  by  the   pul- 

..  L.      ,  monarv    and    general     condition.       As     in 

Method  -  r       1  !  , 

advanced  cases  or   pulmonary  tuberculosis, 

tuberculin  cannot  be  expected  to  cure;  this 
thereto.  can   still   less   be   hoped   for  when    there   is 

any  considerable  disease  in  so  important  an  organ  as  the  larynx 
as  a  complication.  The  indication  for  the  specific  treatment  of 
laryngeal  tuberculosis  is  therefore  similar  to  that  for  surgical 
treatment ;  it  should  not  be  attempted  when  and  so  long  as  the 
prognosis  of  the  underlying  pulmonary  disease  is  unfavourable. 
..        .     ,  .  Ed.    Meyer    [263],    who    concurs   with    our 

.  .  views,   considers  the  following  local  condi- 

ondi  ions.  tions    unsuitable  :     very    severe    and    pro- 

nounced laryngeal  changes,  accompanied  by  miliary,  dis- 
seminated nodules ;  cases  with  symptoms  of  stenosis  when 
stricture  and  danger  of  suffocation  are  not  relieved  by  operation  ; 
cases  with  a  strong  tendency  to  breaking  down  of  infiltrations, 
in  which  there  is  very  probably  a  mixed  infection.  On  the  other 
hand,  it  is  immaterial  whether  the  tubercular  changes  take  the 
form  of  infiltration,  ulceration,  or  perichondritis,  or  a  combination 
of  these  three  forms. 


236  TUBERCULIN     IN     DIAGNOSIS     AND     TREATMENT 

Since  the  aim  is  in  general  to  produce  local  reaction  at  the 

seat   of   disease   and   avoid   general    reaction,    the   possibility   of 

control   by   means   of   the    laryngoscope   is   an    advantage   to   be 

made  use  of  after  each  injection.     In  one  respect — the  possibility 

of   inspection    of   the   actual    disease   and    of    the    effect   of   each 

injection — the  treatment  has  a  palpable  advantage  over  that  of 

pulmonary  tuberculosis.     But  this  is  prejudiced  because  in   the 

vast    majority    of    cases    the    occurrence    of    a    general    reaction 

conditioned  by  the  main  disease  regulates  the  treatment. 

.  .     .  The  effect  of  tuberculin  on  the  larynx  alone 

Limit  to  ,.rr-      l4.  ■     1  •  .,        •    -     .. 

is    difficult    to    judge,    since    the    injections 

Kesults.  have  always  to  be  made  with  reference  to 

the  pulmonary  condition.  And  in  considering  results  it  must 
be  borne  in  mind  that  the  prognosis  of  laryngeal  tuberculosis 
is  dependent  on  that  of  the  underlying  disease.  Hence  certain 
limits  are  set  to  the  development  of  the  curative  action  of  tuber- 
culin on  the  larynx.  This  action  may  be  seen  at  its  best  when 
a  severe  laryngeal  affection  is  associated  with  a  slight  pulmonary, 
when,  therefore,  the  laryngeal  mischief  is  the  important  one. 
A  freer  hand  is  then  given  in  the  production  of  local  reactions, 
and  if  these  are  not  well  enough  marked  with  the  mild  method 
of  injection,  resort  may  be  had  to  more  powerful  reactions  without 
being  hindered  by  the  pulmonary  disease. 

.  _  But  as  laryngeal  tuberculosis  almost  always 

Long  Treatment  . 

*  follows    advanced    pulmonary    tuberculosis, 

Necessary.  the    resuit    Qf    tne    tuberculin    treatment    is 

generally  not  immediately  perceptible.  For  the  incomparablv 
larger  mass  of  the  diseased  pulmonary  tissue  attracts  to  itself 
the  whole  or  the  greater  part  of  the  tuberculin  injected  by  its 
avidity,  especially  in  the  first  period  of  the  treatment,  and  only 
allows  it  to  act  on  the  larynx  after  it  has  gradually  become 
"  saturated."  To  achieve  real  cures,  therefore,  in  severe  cases 
long  treatment  with  tuberculin  is  necessary,  in  which  large  doses 
must  be  reached.  This  explains  the  good  results  obtained  in  the 
first  era  of  tuberculin,  quoted  by  good  authorities.  Therefore 
we  are  not  astonished  that  those  authors  who  now  are  in  favour 
of  small  and  the  most  minute  doses  at  long  intervals,  or  whose 
opinion  is  based  on  the  short  cures  of  the  public  sanatoria,  have 
seen  no  results  from  tuberculin. 

Choice  of  ^  t^ie  suPeri°ritv  or   Koch's  preparations 

0  ..  there  is  no  reliable  and  sufficient  evidence : 

Preparation;  .  ,       ,,    ,  .     , 

.  with    all    kinds    01    tuberculin    satisfactory 

*  results   have   been   attained.      Even    during 

Kesults.  t|ie   fjrst   tuberculin    era,    C.    Gerhardt   and 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  237 

B.  Fraenkel  reported  good  curative  effects,  so  that  the  latter  has 
never  ceased  to  use  tuberculin.  At  the  International  Laryngeal 
and  Rhinological  Congress  at  Berlin  in  iqii,  B.  Fraenkel  stated 
that  he  never  had  to  suspend  treatment  with  tuberculin  and  had 
had  favourable  results  throughout.  His  last  success  was  the  cure 
of  apical  and  laryngeal  tuberculosis  of  a  pregnant  woman  in  the 
sixth  month.  At  the  same  Congress,  Grabower  declared  that 
since  1891  he  had  had  consistent  good  results  with  tuberculin, 
especially  in  disease  of  the  posterior  wall  and  not  too  severe 
ulcerations.  Moritz  Schmidt  used  old  tuberculin  with  good 
effect,  especially  in  ulcerations  and  lupus  of  the  larynx.  After 
him  P.  Krause  characterized  it  as  a  sin  of  omission  not  to  make 
use  of  tuberculin.  Recently  Moritz  points  out  the  good  effect 
of  old  tuberculin  in  laryngeal  tuberculosis.  Blumenfeld  has  seen 
torpid  ulcers  of  long  standing  completely  heal  which  had  pre- 
viously withstood  all  other  local  treatment — curetting,  cauteriza- 
tion, lactic  acid,  &c.  At  the  Association  of  Sanatorium  Doctors, 
in  191 1,  Brecke  vouched  for  the  value  of  bacillary  emulsion,  even 
in  cases  complicated  by  fairly  severe  pulmonary  disease.  He 
emphasized  the  harmlessness  of  quite  considerable  focal  reactions. 
In  twelve  cases  in  which  the  larynx  was  thus  cured,  the  cure 
was  maintained  after  many  years ;  amongst  them  were  teachers 
and  priests  who  were  able  to  pursue  their  calling.  Willers, 
Polaczek,  and  v.  Zander  also  report  good  results.  From 
England,  too,  most  satisfactory  results  are  reported,  for  example, 
by  Wilkinson,  Williams,  Waggett,  Reik,  Eyre,  K.  and  S.  v. 
Ruck.  Wilkinson  had  such  good  results  that  he  has  abandoned 
all  other  methods.  F.  Krause  prefers  new  tuberculin  bacillary 
emulsion,  Sahli  and  Dluski  Beraneck's  tuberculin.  Ed. 
Meyer  praises  the  good  effect  of  sensitized  tuberculin,  in  severe 
cases  with  the  help  of  local  treatment.  At  the  Congress  of 
German  Throat  Specialists,  in  191 1,  he  gave  details  of  twentv- 
three  cases  [263]  which  proved  a  striking  testimonv  for  the 
value  of  the  combined  specific  and  endolaryngeal  surgical  treat- 
ment, for  the  most  part  results  which  he  had  never  previously 
observed  without  tuberculin.  These  successes  were  the  more 
noteworthy  as  they  are  obtained  partly  in  out-patients  living  and 
working  under  unfavourable  hygienic  conditions.  F.  Kraus 
speaks  highly  of  the  action  of  sensitized  bacillary  emulsion  in 
combination  with  iocal  treatment  in  cases  complicated  by  pul- 
monary tuberculosis,  even  when  the  conditions  are  very  difficult 
(e.g.,  diabetes),  although  the  change  for  the  better  was  often  but 
temporary  owing  to  the  progressive  general  tuberculosis.  Killian 
considers   these   very   noteworthy   results.      F.    Mever   [264]    has 


2^8  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

observed  excellent  results  in  laryngeal  tuberculosis  without 
extensive  infiltration,  and,  in  addition  to  old  tuberculin,  recom- 
mends albumose-free  tuberculin,  bacillary  emulsion,  and  sensitized 
bacillarv  emulsion,  the  latter  with  subsequent  old  tuberculin 
treatment  especially  in  severe  cases.  We  have  had  great  success 
with  Koch's  preparations,  with  bovine  tuberculosis,  and  lately 
also  with  sensitized  bacillary  emulsion. 

.  .   £  ,  ,  Warnings,  however,  are  not  lacking;  against 

Unfavourable         ,  "  '       ,  -.  ,       , 

the    use   of    tuberculin    in    laryngeal   tuber- 
Reoorts 

^         '  culosis.     Several   authors  are  more  or  less 

opposed  to  it  or  sceptical  {e.g.,   Moeller,   Besold  and  Gidionson, 

W.  Neumann,  Barwell,   Lockard).       Friedrich  warns  against  its 

use.     Even   Kraemer,  who  is  otherwise  quite  in  agreement  with 

us,    is    inclined    to    reject    it.     Schroeder,    who    not    long    since 

reported  striking  tuberculin  cures  with  bacillary  emulsion  (out  of 

eight  cases  six  cures  and  one  improvement),  a  little  later  got  the 

impression  that  tuberculin  is  hardly  any  use  and  that  in  manv 

cases  it  even  led  to  the  spreading  of  the  process  in  the  larynx  and 

to  the  breaking  down  of  the  infiltrations.     But  a  change  of  opinion 

in   so   short  a   time   hardly   speaks   for  trustworthy  and   reliable 

judgment. 

Authors'  According     to     our     experience,     cases     of 

-  .  .  laryngeal   tuberculosis   of   slight  and  mod- 

Favourable  "      &  -x  Ml       fx         1  J  1 

erate  seventy  will  often  be  cured  or  vastly 

Experience.  improved  by   sufficiently   long  and  correct 

tuberculin  treatment,  often  without  the  use  of  any  astringent  or 

disinfectant  remedies. 

Areas  of  redness  and  swelling,   localized  or  diffused,   often 

completely  disappear. 

-r       .  r        Small    infiltrations    are    absorbed    without 

Treatment  of       ,  . 

leaving     any     sign ;     larger     ones     require 

longer    time,    according    to    their    position . 

Infiltrations;  jn  typical  infiltrations  of  the  posterior  wall, 

there  frequently  remain  dense  thickenings.     When  these  are  not 

too  large,  curette  and  cautery  may  be  dispensed  with.     Sometimes 

these    infiltrations    break    down,    especially    when    this    was    on 

the    point    of    happening    spontaneously    and    absorption     was 

no    longer    possible.     But    to    deduce    from    this,    as    has    been 

done,    evidence    of    harm    done    by    tuberculin,     is    merely    an 

instance  of  thoughtless  antagonism.     The  experienced  clinician 

knows     that     the     floor     of     the     resulting     ulcer    cleans      with 

remarkable  rapidity,  and  is  soon  covered  in  by  growth  from  the 

edges.     In     many     cases     of     diffuse     infiltrations     which     have 

obstinately    resisted    medical     and     surgical     treatment,      some 

measure  of  restoration  will  be  obtained. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  239 

In  cases  of  slight  ulceration,  too,  we  have 

of  Ulceration  ;       increasingly  given  up  all  caustic  remedies, 

the  more  experience  we  have  had  of  the  action  of  tuberculin.    With 

dirty    ulcers    we    are    in    the    habit    of    insufflating    first    with 

disinfecting  powder  until  the  base  is  clean,  and  then  beginning 

with    the    tuberculin    injections    or    combining    the    two.     Small 

ulcerations  soon  show  a  clean  base,  cast  off  sloughing  edges,  and 

rapidly  become  covered  with  epithelium.     In  the  case  of  larger 

ulcers  with  deeply  undermined  edges,  if  the  sloughs  are  not  cast 

off  with   sufficient   rapidity   on   continuing   the   treatment,    resort 

may  be  had  to  the  scissors  or  galvano-cautery,  or  to  applications 

of  lactic  acid;  by  judicious  combination  striking  results  can  be 

obtained   in    cases   where    the    underlying    disease    is   capable    of 

substantial  betterment. 

.  ....  ,  In  cases  of  severe  and  widespread  infiltra- 

of  Widespread         .  ,,  ,  .    ,  ,  , 

r  tion     or     other    deep     tubercular    changes, 

Disease .  especially       perichondritic       inflammation, 

Perichondritis.  operative  treatment  cannot  be  avoided. 
But  here  treatment  must  often  be  limited  to  relief  of  symptoms 
on  account  of  the  serious  nature  of  the  underlying  disease.  Of 
tuberculin  treatment  in  severe  cases  of  this  sort  we  have  no 
personal  experience.  Such  cases  we  should  prefer  to  exclude 
from  specific  treatment,  especially  as  they  are  generally  accom- 
panied by  the  graver  forms  of  pulmonary  disease  and  there  is 
no  reasonable  expectation  of  improvement. 

To  sum  up,  recent  experience  has  established — and  we  have 
contributed  thereto  by  the  publication  of  several  cases  of  the  cure 
of  severe  laryngeal  disease — that  with  the  help  of  tuberculin  our 
results  may  be  markedly  improved,  and  that  tuberculin  deserves 
to  be  employed  in  the  treatment  of  larvngeal  affections  more  than 
has   hitherto   been   the   case.     However,    we    have    never   recom- 

_       ,  .      ..  ...     mended     reliance     upon     tuberculin     alone 

Combination   with    .       ,  ,  ,  ,    ,    ,  , 

in  the  treatment  of  larvngeal  tuberculosis. 

It  is  remarkable  that  this  erroneous  con- 
Measures,  ception  is  current  among  our  opponents. 
Owing  to  the  enormous  importance  of  testing  the  capabilities 
of  tuberculin  in  the  treatment  of  laryngeal  tuberculosis  in  general 
practice,  in  which  it  is  generally  used  too  little,  we  have,  indeed, 
for  many  years  devoted  ourselves  quite  specially  to  this  study ; 
nevertheless,  our  standpoint  as  regards  laryngeal  tuberculosis 
also  is  that  general,  local,  and  tuberculin  treatment  must  be 
used  to  aid  and  assist  each  other  just  as  we  have  recommended 
in  pulmonary  tuberculosis  the  combination  of  the  best  proved 
methods. 


24O  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

Of  fundamental  importance  also  for  the 
Other  Treatment,  tuberculin  treatment  of  laryngeal  tubercu- 
losis is  rest  of  the  larynx,  and  this  is  best  obtained  by  forbidding 
unnecessary  speech  and,  whenever  possible,  by  absolute  silence. 
Strict  discipline  in  suppressing  cough  is  a  necessary  adjuvant, 
irritation  being  lessened  or  abolished  by  the  internal  exhibition 
of  narcotics  and  by  inhalations. 

With  regard  to  the  general  treatment  of  laryngeal  tubercu- 
losis, the  rules  hold  which  we  have  given  in  describing  the  com- 
bination of  tuberculin  treatment  with  other  methods  for  pulmonary 
tuberculosis. 

_        ...        r       Recently  the  demand  has  been  made  that 
Prophylaxis  of  J  .         ,       ,  ,  t  .,         , 

r  greater  attention  should  be  paid  to  the  pro- 

aryngea  phylaxis  of  laryngeal  complications  in  cases 

Tuberculosis.  0f  pulmonary  tuberculosis,  and  it  is  in 
tuberculin  that  we  possess  such  a  prophylactic  remedy.  By 
lessening  or  abolishing  the  cough  irritation  it  prevents  mechanical 
and  inflammatory  injury  of  the  surface  of  the  larynx,  as  well  as 
the  depositing  of  sputum  in  its  lumen.  But,  above  all,  by  its 
biological  action  it  raises  the  resistance  of  the  tissues  of  the  larynx 
to  infection. 

The  prophylactic  value  of  tuberculin  will  be  specially  realized 
when  the  standpoint  is  taken  that  laryngeal  tuberculosis  is  due  to 
infectious  contact,  because  tuberculin  by  making  expectoration 
easier  arid  loosening  the  sputum  lessens  the  opportunities  for 
infection  by  the  collection  of  sputum  in  the  larynx.  Albrecht's 
recent  experiments  in  rabbits  point  to  the  fact  that  laryngeal  tuber- 
culosis especially  in  its  typical  form  is  caused  in  the  vast  majority 
of  cases  by  infectious  contact  with  the  sputum  ;  that  the  tubercle 
bacilli,  after  superficial  injury  and  loosening  of  the  epithelium, 
pass  through  it  into  the  submucous  tissue.  Hematogenous 
infection  is  certainly  possible,  but  limited  to  a  few  atypical  forms ; 
experiments  as  to  infection  through  the  lymphatic  vessels  have 
given  negative  results ;  the  question,  therefore,  as  to  the  possi- 
bility of  the  occurrence  must  remain  open. 

Weill  reports  a  favourable  and  rapid  action 
s  o  t>erum.  Qn  sijo-ht  and  also  moderately  severe  cases 
of  laryngeal  tuberculosis  from  the  use  of  Marmorek's  serum. 
According  to  Jereslaw  the  serum  was  tried  in  a  series  of  cases  of 
pulmonary  tuberculosis  in  the  sanatorium  of  Loslau,  but  the 
results  were  so  unsatisfactory  that  it  is  no  longer  employed  there. 
Yet  laryngeal  tuberculosis  present  at  the  same  time  was  sometimes 
quite  favourably  influenced.  The  twelve  cases  reported  are  not 
very  convincing  as  the  results  might  be  attributed  to  the  general 
and  local  treatment  which  was  used  at  the  same  time. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  24I 

3.— TUBERCULOSIS  OF  THE  DIGESTIVE  ORGANS. 

Michelson,     v.     Renvers    and     Rosenberg 
Kharynx.  have  obtained  complete  cures  of  pharyngeal 

tuberculosis  by  means  of  tuberculin.  According  to  Blumenfeld, 
tuberculin  is  indicated  in  ulcers  of  the  pars  oralis  which  are  of 
favourable  prognosis,  the  patient  possessing  relatively  good  general 
condition,  in  which  the  pharyngeal  tuberculosis  is  thus  generally 
discovered  at  an  early  stage.  Those  cases  of  unfavourable 
prognosis  are  contra-indicated  in  which  the  disease  is  of  a  miliary 
nature  and  the  process  is  one  of  rapid  degeneration.  Ed.  Meyer 
and  Lesser  cured  a  case  of  rough,  nodulated  infiltration  of  the 
uvula  and  palatine  arch  in  which  miliary  nodules  were  observed, 
by  means  of  sensitized  bacillary  emulsion  and  simultaneous  local 
surgical  treatment,  also  the  apical  pulmonary  and  laryngeal 
disease  present  were  healed  and  the  necrosing  infiltration  of  the 
cords  partly  cured.  Schnitzler  successfully  treated  tumours  of  the 
pharynx  and  naso-pharynx  formed  by  numerous  masses  of 
tubercles  by  means  of  local  tuberculin  treatment ;  the  tumours 
disintegrated,  and  there  were  formed  fairly  large  and  deep  ulcers 
which  showed  an  unmistakable  healing  tendency  partly  by 
beginning  to  skin  over  and  cicatrize,  and  partly  by  the  formation 
of  clean  and  healthy  granulations. 

Trautmann  has  given  details  of  tuberculin 
cures  in  tuberculosis  of  the  tonsils;  when 
there  are  febrile  symptoms,  increased  swelling  of  the  hyper- 
plastic tonsils  takes  place,  which  after  further  injections  re- 
cedes and  gives  place  to  healing,  but  onlv  after  some  months' 
treatment. 

Ludus  of  Mouth      Tuberculin    has   also   proved   of   service    in 

.  lupus    of    the    mucous    membrane    of    the 

and  ,  ,       , 

_,  mouth    and    pharynx.        Improvement    has 

Pnaryngea     Mucous  t  u  a  u     r>     i         t>  •  r>       i 

7    6  been   observed  by  Becker,   Bneger,   Burck- 

Membrane.  hardt,     Heymann,     Hovell,     Krause,     and 

others.  Heuck  completely  cured  a  case  of  extensive  lupus  of  the 
soft  palate,  Kayser  one  of  the  gums,  using  large  closes  of  tuber- 
culin. According  to  A.  Neisser,  the  tendencv  to  heal  in  lupus  of 
the  mucous  membrane  of  mouth  and  pharynx  is  recognizable 
earlier  than  in  facial  lupus  of  simultaneous  occurrence,  although 
complete  cure  generally  requires  subsequent  light  treatment. 

E.     Fischer    and    Petruschky    have    cured 
tuberculosis  of  the  stomach  with  tuberculin. 
With  the  lack  of  any  other  causal  treatment  it  deserves  a  trial  as 
long  as  the  primary  disease  is  not  hopeless. 
16 


242  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

Success  with   tuberculin   in   tuberculosis  of 
"     °     '         other  portions   of   the   digestive  tract   have 
Intestines,  Pancreas,  nQt  yet  been  recorcieci.       It  seems  probable 
and   Liver.  that  in  tuberculosis  of  the  oesophagus,  intes- 

tines, pancreas  and  liver,  almost  always  of  unfavourable  pro- 
gnosis, specific  treatment  can  hardly  be  of  avail.  However,  it 
might  be  tried  as  an  accessory  remedy  when  the  primary  disease 
does  not  exclude  improvement  and  the  treatment  has  no  general 
contra-indication.  As  a  rule  in  intestinal  tuberculosis,  the 
advanced  pulmonary  disease  stands  in  the  way  of  a  tuberculin 
cure. 

4.— TUBERCULOSIS  OF  THE  UROGENITAL  ORGANS. 

The   specific   treatment   of   urogenital   tuberculosis   has  only 

emerged  from  the  experimental  stage  during  the  last  few  years 

since  it  has  been  more  fully  recognized  in  the  province  of  other 

localizations  of  the  disease.     This  is  also  partly  because  urogenital 

tuberculosis   chiefly   falls   under  the   scope  of   operative   surgery 

and  gynaecology,   and   that  a  conservative   standpoint   has  only 

lately  begun  to  win  ground,  in  which  specific  treatment  certainly 

takes  first  place  as  an*  aid  to  hygienic-dietetic  methods.     Present 

reports  of  the  value  of  tuberculin  are  very  variable  in  the  various 

localizations   of  urogenital   tuberculosis.      And   further,    isolated 

tuberculosis  in  most  of  the  organs  as  a  single  clinical  disease, 

especially  in  the  male,  does  not  occur.     However,  the  results  of 

specific'  treatment,    as   far   as   these   have   been    recorded   in    the 

literature  of  the  subject,   will  be  described  separately  under  the 

various  organs  with  a  common  description  for  the  urinary  organs 

of  both  sexes. 

Urethra  There  are  no  separate  reports  of  the  specific 

^  .        treatment  of  urethral  tuberculosis.     Also  in 

Prostate,  and  ,  ,     .      .   ,  ,  ,    L  , 

"  .  tuberculosis  of  the  prostate  there  are  but  tew 

experiences  recorded,  such  as  those  of  von 
Semmales.  Hesse.       We  agree  with  the  standpoint  of 

Casper  who,  including  this  in  the  question  of  the  specific  treat- 
ment of  tuberculosis  of  the  vesicular  seminales,  advises  a  trial  of 
tuberculin  first  of  all,  and  at  any  rate  before  surgical  measures 
as  an  aid  to  conservative  treatment. 

...     ^      ;    '.        The  value  of  tuberculin   in  tuberculosis  of 
Male  Genital         ,  ■  ,     .  ,    . 

the  male  genital   glands   is  a  proved   tact. 

an  In    tuberculosis    of    the    testicle,    excellent 

results  have  been  obtained  by  Lenzmann,  Ullmann,  Pogue,  Kehl, 

E.  R.  W.  Frank,  and  K.  and  S.  von  Ruck.     Karo  cured  a  tuber- 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  243 

cular  fistula  of  the  testicle  with  tuberculin,  which  had  been  treated 
for  some  months  with  Marmorek's  serum  without  avail.  Joch- 
mann  had  favourable  results  in  three  cases  of  tuberculosis  of  the 
epididymis. 

In    tuberculosis    of    the    bladder,    which    is 
bladder,  always   secondarily   infected   from  the   kid- 

neys or  genital  glands,  tuberculin  is  being  increasingly  recom- 
mended by  many  authorities.  Jochmann  had  very  favourable 
results  in  two  cases,  Pogue  in  four  cases,  and  Hesse  in  one  case. 
Birnbaum,  in  four  cases,  obtained  one  certain  and  one  probable 
cure,  and  two  were  considerably,  improved.  Schroeder  cured 
one  case  and  improved  another.  Roth  was  able  to  prove 
cystoscopically  the  healing  of  ulcers  in  the  bladder  after 
tuberculin  treatment.  Suter,  on  the  other  hand,  in  two  cases 
of  tuberculosis  of  the  bladder  after  previous  operation  on  the 
kidney,  observed  no  local  improvement ;  a  third  patient  suffer- 
ing from  genital  and  bladder  tuberculosis  following  nephrectomy 
died. 

The  subject  of  the  specific  treatment  of  renal 
1      ey.  tuberculosis    is    a    matter    of    considerable 

discussion,  particularly  with  regard  to  the  question  of  whether  a 
case  of  unilateral  tuberculosis  must  on  principle  be  operated  on 
or  whether  this  may  be  postponed  and  specific  treatment 
employed.     The  present  state  of  opinion  is  as  follows  :  — 

_    .    .  .         Israel,      while     recognizing     the     valuable 

Opinions:  of  ,    .  , °     ,     °     .         ,. 

r  .         .  action  of  the  remedy,  demands  extirpation 

I  crgpl  "  J 

of  the  kidney  when  only  one  is  affected 
and  the  bladder  healthy,  reserving  tuberculin  treatment  for  cases 
of  double  affection,  for  after-treatment,  or  when  operation  was 
refused — a  standpoint  also  taken  up  by  Knorr. 

Casper  [265]  demands  operation  whenever 
sper  '  possible,    especially    in    advanced    tubercu- 

losis of  one  kidney.  Operation  is  contra-indicated  in  cases  of 
pronounced  general  tuberculosis,  simultaneous  genital  tubercu- 
losis, and  in  cases  where  the  Second  kidney's  functions  are  no 
longer  normal ;  here  tuberculin  treatment  can  be  employed,  which 
he  has  proved  to  be  specially  useful  in  tuberculosis  of  the  bladder 
after  the  diseased  kidney  has  been  removed. 

Karo  [266]  sums  up  his  verdict  by  stating 
aro  '  that   Koch's  old  tuberculin   often   produces 

a  complete  cure  in  the  initial  stages  of  tuberculosis  of  the  kidneys. 
Specific  treatment  in  the  early  stage  of  the  disease  is  also  to  be 
preferred  because  it  is  of  a  secondary  nature  and  after  successful 
nephrectorm'  the  second  kidnev  often  becomes  infected  from  the 


244  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

primary  focus  (three  personal  observations  in  the  course  of  one 
year).  The  great  importance  of  the  specific  treatment  lay  in  the 
fact  that  it  not  only  cured  the  tubercular  kidney  but  also  the 
primary  focus,  and  so  prevented  the  infection  of  the  other  kidney. 
He  had  cured  or  radically  improved  twelve  cases  with  tuberculin. 
According  to  Karo,  tuberculin  treatment  is  also  indicated  in  all 
cases  when  both  kidneys  are  diseased.  Moreover,  tuberculin 
treatment,  after  removal  of  the  primarily  diseased  kidney  by  opera- 
tion, assists  the  natural  cure  of  the  bladder  and  genital  organs 
affected  by  tuberculosis. 

Mantoux  [267]  expresses  almost  the  same 
Mantoux ,  opinion,  based  on  seventy  cases  of  tubercu- 

losis of  the  urinary  apparatus  collected  from  the  literature.  33  per 
cent,  were  cured,  48  per  cent,  appreciably  improved.  Various 
kinds  of  tuberculin  produced  the  same  effect.  The  treat- 
ment must  be  strictly  individual  and  reactions  most  carefully 
avoided.  Simultaneous  general  and  local  treatment  aids  in 
effecting  a   cure. 

Kornfeld's  work  is  also  specially  valuable. 

e  a.  As  a  result  of  a  general  inquiry  conducted 

by  him,  he  considers  the  prognosis  of  tuberculosis  of  the  kidneys 

to  be  most  satisfactory  and  hopeful   when   the   hygienic-dietetic 

treatment  is  combined  with  tuberculin  treatment. 

~..        ,-  ,  .        Leedham-Green  has  published  three  cases  of 

Other  Favourable  ......      r       r         , 

cures  in  the  initial  stage  of  renal  tuberculosis 

"         '  in  children  ;  Pedersen  of  clinical  healing  in 

two  cases  of  tuberculosis  of  kidneys  and  bladder  which  remained 
free  from  symptoms  one  and  two  years  respectively  after  treatment. 
Teissier  observed  tuberculin  cure  in  a  case  of  bilateral  renal  tuber- 
culosis, Schultze  considerable  improvement  in  tuberculosis  both 
of  the  kidneys  and  bladder.  John  Pardoe  obtained  favourable 
results  without  resorting  to  any  other  method  of  treatment ;  of 
twenty-one  cases  five  were  cured  and  four  distinctly  improved. 
Pielecke,  Jochmann,  Keersmaecker,  Kneise  and  Heinemann  also 
obtained  satisfactory  results ;  Prochownik  cessation  of  all  sym- 
ptoms and  general  well-being  of  three  patients  for  three  to  ten 
years.  The  experiences  of  the  medical  clinic  at  Giessen,  too, 
which  Hohlweg  has  recently  published,  are  important.  Four 
patients  suffering  from  advanced  bilateral  disease  with  more  or 
less  severe  symptoms  in  the  bladder  for  whom  operation  was  no 
longer  possible  were  treated.  In  all  these  the  subjective  sym- 
ptoms were  almost  suppressed,  and  a  considerable  objective 
improvement  was  made,  while  one  was  almost  completely 
cured. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  245 

.  .   s  ui  In  contrast  to  these  favourable  experiences, 

Unfavourable        T^  ,  .  r  , 

Kumrnell   could   see   no   curative  action   ot 

"  tuberculin    in    tuberculosis    of    the    kidney. 

Kumrnell,  Kraemer,  therefore    he    recommends    that    no    time 
and  Suter.  should    be    wasted    in    tuberculosis    of    one 

kidney,  but  that  there  should  be  an  operation.  He  would  only 
permit  of  tuberculin  treatment  in  children.  He  takes  up  this 
standpoint  because  in  four  cases  which  had  been  treated  up  to 
one  and  a  half  years  with  tuberculin,  he  found,  partly  on  opera- 
tion, partly  post  mortem,  extensive  tuberculosis  of  the  kidneys. 
F.  Kraemer  also  found  in  the  extirpated  kidney  of  a  patient  who 
had  been  treated  for  seven  months  with  tuberculin,  fresh  tubercles, 
the  formation  of  which  had  not  been  prevented  by  the  tuberculin. 
Suter  records  a  case  in  which  increasing  deterioration  of  the  con- 
dition in  spite  of  over  a  year's  tuberculin  compelled  extirpation 
of  the  kidney,  which  brought  about  a  cure.  Unfortunately 
nothing  definite  is  said  as  to  the  method  of  treatment,  on  which 
of  course  everything  depends. 

_      ,        ,  .        Bachrach  and  Necker,   in  conjunction  with 

Bachrach  and        ,„.,,,    ,        ,  ,  .  r        •    ,  .         , 

Wildbolz,  observed  increase  of  weight  and 

Necker  s  Method,    improvement  of  the  general   condition   but 

no  local  healing  action  ;  they  consider  that  the  value  of  tuberculin 

treatment  lies  in  the  tox-immunity  of  the  organism.       Bachrach 

and  Necker  recommend  a  reactionless  treatment  for  early  cases, 

until  there  is  an  indication  for  nephrectomy,  for  tubercular  cases 

in  whom  nephrectomy  has  been  performed  in  which  foci  in  the 

urogenital  system  or  other  organs  remain,  and  also  that  it  should 

be  tried  in  inoperable  cases  in  the  absence  of  any  more  efficacious 

remedy. 

The  desirability  of  treatment  with  tuberculin  after  operation 
on  the  kidney  receives  general  recognition. 

Lenhartz  is  particularly  warm  in  his  general 

en   artz.  recommendation   of  tuberculin   for  diseases 

of  the  urogenital  apparatus.    He  claims  that  tuberculin  treatment 

must  precede  surgical  measures,  as  he  has  seen  absolute  healing 

with  the  former  even  in  severe  cases. 

Fr.  Miiller  and  Stintzing  have  also  quite  recently  expressed 
their  general  recognition  of  the  value  of  tuberculin  in  the  treat- 
ment of  urogenital  tuberculosis. 

_,  .  At  the  International  Congress  on  Tubercu- 

Bevan  and  ,  ,,,.     ,.  ^  , 

losis    in    Washington,    Bevan    recommends 

P"  the  combination  of  surgery  and  tuberculin 

treatment.     Philip  recognizes  the  power  of  tuberculin  as  follows  : 

Tuberculin  can  take  the  place  of  surgery  :  — 


246  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

(1)  In  certain  cases  in  which  a  topical  diagnosis  cannot  be 
made  with  certainty,  or  when  the  result  of  the  operation  is  either 
doubtful  or  fruitless. 

(2)  In  a  number  of  non-operable  cases  on,  for  example, 
extensive  tuberculosis  of  the  urinary  and  sexual  organs,  in  which 
a  radical  operation  is  impossible. 

,  Lelongt  gives  a  general  recommendation  of 

e  ong   s  tuberculin    for   all    urogenital    tuberculosis; 

Recommendation.  he  states  that  in  many  cases  a  cure  is 
obtained,  improvement  is  almost  always  seen,  and  with  correct 
technique  aggravation  of  the  condition  is  a  rare  occurrence.  It 
is  specially  indicated  in  vesical  tuberculosis,  in  tuberculosis  of  the 
male  genital  organs,  in  bilateral  and  commencing  unilateral  renal 
tuberculosis,  and  in  a  recurrence  of  renal  tuberculosis  after  extir- 
pation of  one  kidney. 

The  introductory  notes  to  this  chapter  have 

a  special  significance  in  tuberculosis  of  the 
Genital  Organs.  femaie  genital  system.  Here  the  advocates 
of  surgical  and  conservative  methods  are  very  definitely  in  oppo- 
sition. It  is  natural  that  those  who  recommend  radical  operative 
measures  are  much  more  reserved  towards  the  question  of  specific 
treatment  than  those  who  recommend  conservative  methods.  In 
the  former  case  the  opinion  is  that  the  use  of  specific  remedies  is 
only  permissible  when  operative  gynaecology  has  reached  the 
limit  of  its  capacity.  This  assumes  that  specific  treatment  is  not 
to  be  tried  in  cases  of  tuberculosis  of  the  female  genitals  of 
favourable  prognosis.  It  is,  at  any  rate,  certain  that  present  ideas 
of  the  value  of  specific  therapy  in  this  branch  of  medicine  are  too 
limited.  Advocates  of  the  conservative  method  take  up  the  stand- 
point based  on  their  experience  that  conservative  treatment  holds 
out  greater  prospects  of  success  the  earlier  it  is  combined  with 
specific  treatment.  Thus  Veit,  for  example,  strongly  recom- 
mends tuberculin,  from  the  use  of  which  he  has  seen  far  better 
results  than  from  operative  measures. 

The  treatment  of  tuberculosis  of  the  vagina, 
=>       *  usually  of  a  secondary  nature,  is  regulated 

by  the  primary  disease  of  the  genital  organs,  on  the  extent  and 
prognosis  of  which  the  result  of  the  former  depends.  Where 
operation  does  not  appear  to  be  indicated,  Veit  states  that  the 
best  general  treatment  is  the  hvgienic-dietetic  combined  with 
tuberculin. 

.  In  isolated  tuberculosis  of  the  uterus  there 

are  few  reports  of  specific  treatment.    Seelig- 
man  gives  a  favourable  verdict. 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        247 

In   tuberculosis  of  the  appendages  reports 

Appendages.  are  rather  more  numerous,  and,  as  a  rule, 
decidedly  satisfactory.  The  following  are  the  most  important 
recorded  in  the  literature  of  the  subject,  and  are  not  confined  to 
this  localization  alone,  but  also  relate  to  disease  of  other  genital 
organs  usually  combined  with  it. 

Prochownik  [138]  reports  great  success  with  tuberculin  in 
twenty-two  cases  of  female  genital  tuberculosis,  in  which  he 
obtained  complete  cure  or  a  lengthy  standstill  (up  to  fifteen  years). 
The  larger  tubercular  tumours  must  be  operated  upon ;  in  general, 
however,  he  is  in  favour  of  prolonged  conservative  treatment  of  a 
general  nature  combined  with  tuberculin.  It  should  be  specially 
noted  that  he  never  observed  local  relapse  in  his  tuberculin 
cases. 

Birnbaum  [137]  has  treated  four  cases  of  tuberculosis  of  the 
appendages  with  tuberculin,  in  which  he  claims  to  have  produced 
complete  cure ;  in  two  cases  there  were  no  longer  any  objective 
symptoms,  and  in  the  other  two  the  symptoms  completely  dis- 
appeared and  the  tangible  objective  condition  spoke  for  a  com- 
plete healing  or  standstill  of  the  process.  Therefore  Birnbaum 
temporarily  dispenses  with  laparotomy  in  tubercular  disease  of 
the  appendages. 

Seeligmann  has  had  success  in  tubercular  pyosalpinx.  Kelly 
observed  great  improvement  in  several  cases  of  genital  tubercu- 
losis. Fritsch  also  believes  in  specific  treatment  on  the  ground  of 
his  own  observations.  Schiller  is  in  favour  of  a  combination  of 
operative  and  specific  treatment  in  genital  tuberculosis. 

Further,  while  Busse  had  almost  uniform  success  with  the 
ambulant  specific  treatment  of  tuberculosis  of  the  appendages, 
Zoeppritz  considers  its  action  unreliable  for  this  disease  in  dis- 
tinction to  its  regular  healing  influence  on  peritoneal  tuber- 
culosis. 

Ziegenspeck  recommends  after-treatment  with  tuberculin 
following  operation  in  genital  tuberculosis.  In  this  way  he 
brought  the  trouble  to  a  lasting  standstill  in  tubercular  pyo- 
salpinx, in  one  case  with  advanced  tuberculosis  of  the  abdominal 
walls. 

t-   ,  ...  In  conclusion,  attention  must  once  more  be 

Tuberculin  in         .  .  „  .  L  . 

drawn  here  to  the  excellent  effect  of  tuber- 

I    I  |hop/^l||ciK* 

culin  on  the  form  of  dysmenorrhcea  caused 
Dysmenorrncea.     j-,y.  tubercular  intoxication  in  manifest  and 
latent  tuberculosis,  which  we  are  able  to  confirm. 

Recently  Grafenberg  [268]  has  studied  these  disturbances  in 


248  TUBERCULIN    IN     DIAGNOSIS    AND    TREATMENT 

detail  at  the  Kiel  University  Women's  Clinic.     He  reports  very 

favourable   results   in   out-patient   cases   of   prolonged   tuberculin 

treatment,    under   which    not   only   the   dysmenorrhceal   but   also 

other    pelvic-peritoneal    symptoms    disappeared.       He    conceives 

primary  dysmenorrhea,   which  is  often  characterized  by  violent. 

local  reactions  of  the  genital  system  as  well  as  general  reaction,  to 

be   inflammatory  dysmenorrhcea   in   local   or  only   latent  genital 

tuberculosis.     The  results  of  tuberculin  treatment  are  all  the  more 

important,  as  in  many  cases  an  operation,  however  trifling,  may 

cause  spreading  of  a  latent  form  of  genital  tuberculosis  (Grafen- 

berg,   Poncet  and  Leriche,    Prochownik) ;  thus  amongst  Grafen- 

berg's  cases  there  were  several  in  which  simple  dilatation  of  the 

laminaria-tents  for  dysmenorrhcea  resulted  in  acute  genital  and 

finally  miliary  tuberculosis. 

~,     .         c  In  the  treatment  of  male  and  female  genital 

Choice  of  ,  .     .  ._  ?     , 

_   ,  ,.  tuberculosis,    no    one    specific    remedy    has 

Tuberculin.  „      ,  ..     u  ■        .   u        ,.        , 

proved  itself  superior ;  tuberculins,  however, 

have  proved  more  valuable  than  serum.     According  to  Lenhartz, 

old   tuberculin    is   preferable    to    new    tuberculin.     Veit    strongly 

recommend^   the   latter.     Wright,    Raw,    Seeligmann,    and  John 

Pardoe    use     TR,     Pedersen    and    Schroder    Koch's    bacillary 

emulsion.     Birnbaum  injects  alternately  new  and  old  tuberculin, 

in  ambulant  practice  only  the  latter.     Jochmann  begins  with  old 

tuberculin  and  completes  the  treatment  with  bacillary  emulsion. 

Sahli  reports  very  favourably  on  Beraneck's  tuberculin,  Le  Clerc- 

Dandoy  on  Denys'  tuberculin.     Great   improvements  have  been 

observed  after  treatment  with    Klebs'   tuberculins,    for   instance, 

by  Roerig  in  vesical  tuberculosis  and  by  Kriiger  in  three  cases 

of  urogenital  tuberculosis. 

_  With    Marmorek's    serum    Schenker    noted 

Serum.  ....  . 

striking     improvement     in     four     cases     of 

disease  of  bladder  and  kidney.  Landau  reports  the  appearance 
of  several  crater-shaped  fistulas  covered  with  considerable  granu- 
lations, which  had  arisen  after  operation  in  tubercular  appendage 
disease,  leading  to  a  wound  as  big  as  a  shilling  in  the  abdominal 
wall,  which  defied  all  treatment.  The  condition  improved  sensibly 
under  Marmorek's  serum  and  the  fistulas  healed  up.  On  the 
other  hand  Karo  [135]  could  not  perceive  any  favourable  action 
by  the  serum  in  any  single  case  of  urogenital  tuberculosis,  so  that 
in  the  end  he  abandoned  its  use,  all  the  more  because  in  one  case 
in  immediate  connection  with  it  a  case  of  miliary  tuberculosis 
occurred  which  ended  fatally.  A  tubercular  fistula  of  the  testicle, 
treated  with  Marmorek  serum  in  vain  for  months,  healed  up 
smoothly  under  tuberculin. 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        249 

5.— TUBERCULOSIS  OF  THE  SEROUS  MEMBRANES. 

Tuberculin  treatment  of  the  pleura  is  con- 
Pleura,  terminous  with  that  of  the  lung.  It  is 
natural  that  the  subject  has  no  separate  literature.  Either  (i)  it 
is  a  case  of  so-called  idiopathic  pleurisy  in  which  pulmonary 
tuberculosis  is  present  in  a  latent  form,  in  which  case  its  etiology 
is  only  clear  after  the  cessation  of  the  acute  inflammatory  and 
febrile  symptoms  and  the  time  for  specific  treatment  of  the  tuber- 
cular pleurisy  is  late  or  past  (as  recent  experience  has  shown 
that  idiopathic  pleurisy  is  followed  in  a  large  percentage  of  cases 
by  pulmonary  tuberculosis,  in  the  future,  specific  treatment  will 
be  more  frequently  considered) ;  or  (2)  pleurisy  occurs  as  a  com- 
plication in  pulmonary  tuberculosis  already  diagnosed.  In  such 
cases  as  long  as  the  dry  pleurisy  is  very  painful  or  the  dry  and 
exudative  form  is  accompanied  by  fever,  specific  treatment  is  not 
indicated.  From  these  considerations  it  is  evident  that  in  tuber- 
cular pleurisy  it  will  generally  be  reserved  for  after-treatment,  for 
which  purpose  we  have  often  found  it  valuable. 

The  value  of  specific  treatment  in  peritoneal 
Peritoneum.  tuberculosis  is  definitely  established. 
Olshausen,  Zweifel,  Fritsch  and  others  reported  favourably  in  the 
first  tuberculin  era,  Fritsch  after  previous  laparotomy ;  lately 
Ganghofner,  Grosz,  Latham,  Wright  in  children,  Fr.  Miiller, 
Chalif,  Alapy,  Ziegenspeck,  Kleinkneckt  in  adults  all  testify  to  its 
efficacy.  Sprengel  obtained  an  extraordinarily  successful  result  ift 
a  case  of  tuberous  peritoneal  tuberculosis.  Birnbaum  [137] 
brought  about  healing  in  all  of  five  cases  with  a  considerable 
amount  of  ascitic  fluid;  of  five  cases'of  dry  tubercular  peritonitis 
he  cured  four.  Zoeppritz  recommends  tuberculin  treatment  in 
peritoneal  tuberculosis  on  Birnbaum's  method;  of  eighteen  cases 
treated  three  to  six  years  previously,  fourteen  were  able  to  work 
(of  which  nine  were  completely  healed),  and  four  had  died.  Busse 
treated  thirty  women  with  old  tuberculin  under  rigid  precautions. 
These  were  cases  of  peritonitis  with  pyosalpinx,  exudative  peri- 
tonitis, diseases  of  the  appendages,  some  of  which  had  been 
operated  upon  and  some  without  previous  surgical  treatment, 
dysmenorrhoea,  and  menorrhagia.  Sixteen  were  cured,  five 
improved,  and  eight  remained  unaffected ;  one  patient  was  lost 
sight  of.  Simple  laparotomy  with  subsequent  old  tuberculin 
treatment  is  also  strongly  recommended  by  the  Breslau  University 
Women's  Clinic  on  the  ground  of  results  in  thirty-six  cases  of 
peritoneal  tuberculosis.  Heimann  [141],  who  records  the  details, 
attributes  the  very  satisfactory  results  (54  per  cent,  cured  after  two 


25O  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

years'  observation)  not  only  to  the  simple  drainage  of  the  fluid, 

but  chiefly  to  the  tuberculin  cure  always  commenced  six  to  seven 

days  after  the  operation.     He  quotes  the  results  of  his  experiments 

on  animals  as  further  proof,  in  which  he  observed  all  the  stages 

of  the  healing  processes  from  the  simple  round  cell  infiltration  to 

the   true  cicatrization    round   the   former   foci   with   simultaneous 

decrease  of  bacilli. 

w     .  New  tuberculin  TR  has  been  used  by  Raw 

Various 

and  Warth,  the  latter  at  the  same  time  per- 
Preparations  Used.  forming  laparotomy. 

By  subcutaneous  injections  of  his  own  tuberculin,  Rosenbach 
completely  cured  a  case  of  exudative  tuberculosis  of  the  peri- 
toneum. A  second  case  with  equally  successful  and  rapid  cure 
is  recorded  by  H.  Curschmann. 

Schenker   cured   an   apparentlv    hopeless   case   of   peritoneal 

tuberculosis  with  Marmorek's  serum. 

_   ,  .  In  the  unfavourable  prognosis  of  tubercular 

Tubercular  .      ...       ..,,.  u     u       a    c       t 

meningitis,    little    can    be    hoped    for    from 

ningi  is.  specific  treatment,   and  in  most  cases  it  is 

even   contra-indicated.       Uhthoff's   report   of   a   cure   bv   specific 

treatment     of     ocular     tuberculosis     complicated     by     tubercular 

meningitis  is  all  the  more  remarkable. 

6.— TUBERCULOSIS  OF  THE  EYE. 

Tuberculin  has  brought  about  such  triumphs  in  ophthalmic 
practice  as  to  call  increasing  attention  to  specific  treatment,  and 
in  this  field  a  considerable  contribution  was  made  towards 
rescuing  the  reputation  of  tuberculin.  The  surprising  cure  of 
the  severest  forms  of  ocular  tuberculosis,  vision  being  retained 
without  the  assistance  of  any  other  therapeutic  measure,  is  in 
fact  so  striking  as  to  exert  a  healing  effect  also  on  the  blindness 
of  the  opponents  of  tuberculin.  Good  results  have  been  recorded 
for  old  tuberculin  (Schoeler,  Leber,  Hummelsheim,  Lindenmeyer, 
Emanuel  and  others),  but  new  tuberculin  deserves  the  preference. 
Small  doses  carefully  graduated  are  employed,  scrupulously 
avoiding  anything  like  a  severe  reaction.  The  possibility  of  fol- 
lowing in  the  eye  the  local  reactions  and  every  step  of  the 
curative  process  makes  the  employment  of  tuberculin  specially 
easy  and  gives  the  clue  to  dosage,  interval,  maximal  dose,  and 
length  of  treatment.  Kriickmann,  Reis  and  Kuhnt  point  cut 
that  it  is  just  those  cases  of  ocular  tuberculosis  which  show 
distinct  local  reactions  to  very  small  doses  of  tuberculin,  which 
derive  great  benefit  from  specific  treatment. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  25 1 

A.  v.  Hippel  [269],  who  has  probably  had 
""  as    much    experience    as    anyone    of    such 

Experience.  treatment,  recently  recommends  new  tuber- 

culin TR  given  by  the  following  method.  He  begins  the  in- 
jections with  a  dose  of  o"2  c.mm.  and  repeats  the  dose  even- 
other  day,  increasing  by  o"2  c.mm.  each  time.  From  2  c.mm. 
upwards  he  increases  the  dose  each  time  by  2  c.mm.,  from 
20  c.mm.  upwards  by  8  or  10  c.mm.  as  long  as  the  temperature 
remains  normal.  If  this  is  raised  above  380  C.  he  injects  the  same 
dose  two  or  three  times  running  and  only  increases  it  again 
when  no  further  general  reaction  appears.  To  go  above 
100  c.mm.  v.  Hippel  considers  superfluous,  as  he  has  succeeded 
in  curing  the  severest  cases  of  ocular  tuberculosis  with  much 
smaller  doses.  He  expressly  warns  against  commencing  treat- 
ment with  too  large  doses,  as  in  some  cases  of  tubercular 
keratitis  he  observed  the  breaking  down  of  corneal  tissue  situated 
over  a  tubercular  nodule  and  the  formation  of  an  ulcer  due  to 
a  local  reaction  of  too  great  severity ;  it  should  be  added,  how- 
ever, that  these  ulcers  soon  healed  after  application  of  a  fomen- 
tation, v.  Hippel's  experience  is  that  to  prevent  relapse  the 
injections  must  be  continued  until  all  nodules  are  replaced  by 
scar  tissue,  the  swelling  and  vascularization  of  the  iris  have 
returned  to  normal,  and  precipitations  on  the  posterior  surface 
of  the  cornea  as  well  as  vitreous  opacities  have  disappeared.  To 
obtain  permanent  cure  in  the  severest  cases  a  period  of  six 
months  or  more  is  required. 

,  ,  r  d      -ii  As  in  some  cases,  in  spite  of  rapid  healing, 

Use  of  Bacillary         ,  1  TT-        ,  T^     1  , 

relapses  occur  later,   v.   Hippel,   at   Koch  s 

suggestion,      commenced     using     bacillary 

emulsion   in    1906.     The   results  obtained  were  similar  to  those 

of  TR.     But  v.    Hippel   now   gives  the   preference  to   bacillary 

emulsion,  because  according  to  his  experiences  up  to  the  present 

it   is  distinctly  less  likely  to  be  followed  by  relapses  than   TR 

(see  Davids,   p.  254).      The  method  is  exactly  the  same  as  with 

TR,    beginning   with    o'2    c.mm.    and    reaching   a    maximum   of 

200  c.mm.;  the  method  is  in  general  the  same  as  that  used  for 

many  years  in  the  Gottingen  University  Eye  Hospital. 

Results  of  Eyre'      v"      HiPPel>       Masing,      Saathoff, 

_.,         _,  v  Schwarz,  Griffith,  and  Vossius  report  cures 

Other  Observers :      c    ,   ,  ,     •       r    .,  ...  t-u 

or    tuberculosis    of    the    conjunctiva.       1  he 

Uonjunctiva  ,  value  of  tuberculin  treatment  in  eczematous 
conjunctivitis  is  generally  recognized ;  Tionen  has  recently  re- 
ported successful  results  in  fifty  cases. 


252  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

Cases    of    corneal    tuberculosis   were    cured 

Cornea;  ^y   Busse,    Dodd,    Emanuel,    Erdmann,    v. 

Hippel,   Laas,   Lichtensteih,    Rohmer,    Saathoff,    Schoeler,    Ull- 

mann  and  Wilder. 

v.    Hippel   and    Brandenburg    report   cures 

Sclerotic.  -n     tuberculosis     of    the    sclerotic,     whilst 

Schoeler  and  Busse  also  saw  good  results  in  tubercular  scleritis 

and  episcleritis.     Reis,   with  a  few  injections  of  old  tuberculin, 

cured  several  cases  of  the  so-called  "  tuberculoma  of  the  bulbar 

conjunctiva,"   which   is   situated    in    the    neighbourhood  of  the 

corneal  margin,  and,  according  to  this  author,  hardly  ever  takes 

its  origin  from  the  conjunctiva  but  from  the  superricial  coat  of 

the  sclerotic. 

,  .  ,    _...  The    conditions    for    healing    are    specially 

Iris   and  Ciliary      ,  ,,      .      ,,  ,        ..  f    •  •" 

1      favourable    in    the    vascular    tissue    of    ins 

Body.  ancj  ciijary  body,   a  fact  confirmed  by  the 

experience    of    M.    Elsasser,    Falkenberg,    Handmann,    Halben, 

Sattler,  Reunert,  v.  Hippel,  Bull,  Stock,  Lichtenstein,  Kraemer, 

Schultz-Zehden,    Brown,    Bulson,    Busse,    Gamble,   Vossius,   and 

others.     We,  too,  can  report  very  favourable  results.     Augstein 

cured  a  case  of  severe  tubercular   iritis,    in   which   the  question 

of     enucleation     had    been     raised,     with     retention     of    vision. 

D'Alessandro  published   the  account  of  a   case  exactly  similar. 

Cramer  obtained  striking  results  in   two  cases  of  severe  serous 

iritis  (one  of  them  after  iridectomy  for  glaucoma),   in  a  case  of 

severe  iridocyclitis  with  diffuse  sclerosing  keratitis  and  vitreous 

opacities,  as  well  as  in  a  patient  with  two  isolated  iridic  tubercles 

complicated  with  a  large  infiltration  in   the  sclerotic. 

Diem     and     Stock     specially     recommend 

oro  tuberculin    in    tuberculosis   of   the   choroid. 

Schoeler,    with   an    exceptionally    large   experience,    attained    for 

the    most    part    substantial    improvement    in    twenty-nine    cases. 

Cramer   observed   the   cure   of   a    large   isolated   tubercle    in    the 

choroid  with   heavy  deposits  on   the  cornea.     Lubowski   reports 

a  similar  case.     Axenfeld,  too,  has  seen  cures  of  tubercle  in  the 

choroid.     Emanuel   records   the   favourable   course   of  a   case   of 

choroiditis  centralis  with  severe  myopia.     Busse's   good   results 

with  TR  include  four  cases  of  choroiditis. 

....  ,.  The    efficacy    of    tuberculin    has    also    been 

Vitreous  Humour,  .    ■  •  1  a  *  u 

proved    in    primary    and    secondary    tuber- 

Ketina,  culosis  of  the  vitreous  humour,   retina  and 

and  Optic  Nerves.   0ptic  nerves,  the  etiology  of  which  has  only 

in  recent  times  been  investigated  and  this  largely  with  the  help 

of  tuberculin.     There  are  many   records   in   the   literature  (e.g., 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  253 

from  Schoeler  and  Igersheimer)  of  complete  and  permanent 
clarification  of  the  vitreous  humour  with  restoration  of  good 
eyesight  after  opacity  and  haemorrhage.  Amongst  others, 
Augstein,  Heerfordt,  Igersheimer,  Pick,  Scheuermann,  Schnau- 
digel,  and  Schoeler  have  obtained  a  definite  healing  action  in 
tubercular  retinitis,  neuritis  optica,  papillitis,  and  retrobulbar 
neuritis.  Many  other  notable  results  have  been  recorded  in 
individual  cases  by  a  large  number  of  other  observers. 

Favourable  results  in  cases,   some  of  them 
almost    hopeless,    are    further    recorded    bv 
Favourable  Axenfeld,    Berry,    Dor,    Erdmann,    Franke, 

Results.  Groenouw,      Hayashi,      Fr.      Miiller,      zur 

Nedden,  Purtscher,  Reuchlin,  Schleich,  Schoeler,  Schumacher, 
Stargardt,  Tillmann,  Wolfram,  Zimmermann,  and  others.  In 
the  Ophthalmic  Clinic  at  Tubingen,  too,  new  tuberculin  is 
extensively  used  on  account  of  the  favourable,  in  part  excellent 
results  obtained.  Augstein  [121]  has  recently  reported  numerous 
favourable  and  rapid  healing  processes  in  severe  cases  not  yield- 
ing to  other  treatment  of  parenchymatous  keratitis,  ulceration  of 
the  cornea,  iridochoroiditis,  with  sympathetic  affection  of  the 
sclerotic,  choroiditic  exudation  with  haemorrhage,  and  iridocyclo- 
choroiditis  with  turbidity  of  the  vitreous  humour. 

The  results  obtained  by  Remy  Tardieu  in  twelve  very 
obstinate  cases  of  varied  forms  of  tubercular  affections  of  the  eye 
in  which  the  usual  specific  treatment  failed  are  equallv  favour- 
able. He  noticed  during  the  treatment  simultaneous  improve- 
ment in  swellings  of  the  glands,  discharge  from  the  ear,  obstinate 
chronic  rhinitis,  facial  lupus,  and  tubercular  periostitis.  He 
used  a  tuberculin  from  the  Pasteur  Institute. 

I_j.        .,  v.    Hippel    (1904)    is    enthusiastic    over    the 

'  value    of    tuberculin    on    the    basis    of    his 

Conclusions.  ,,  ,,        •.,  tt  c  , 

excellent  results  with  it.     He  was  successful 

in  curing  the  severest  forms  of  tubercular  disease  of  the  eye, 
including  several  in  which  blindness  had  already  occurred.  His 
series  includes  twenty-three  cases  of  tuberculosis  of  the  iris, 
ciliary  body  and  cornea,  one  of  the  sclerotic  and  three  of  the 
conjunctiva.  After  eliminating  thirteen  cases  of  cure  which  he 
considers  not  quite  conclusive,  there  remain  ten  cases  which  were 
cured,  and  remained  so  for  a  period  of  nine  and  a  half  years. 
His  conclusions,  giving^  as  they  do  the  general  sense  of  his 
writings,  may  be  quoted  here:  "On  the  basis  of  the  facts 
recorded  by  myself  I  consider  it  proved  that  we  possess  in 
tuberculin  TR  a  remedy  which,  rightly  employed,  can  perma- 
nently   cure    the    severest    tubercular    disease    of    the    eve    with 


254  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

retention  of  vision.     Based  on  this  fact  it  becomes  our  duty,  not, 

as  often   in  bygone  days,   to  enucleate  such  eyes  without  more 

ado,   but  first  of  all  to  attempt  to  combat  the  disease  with  the 

weapons  which  we  owe  to  R.  Koch.     And  we  can  do  this  with 

the   less  hesitation   as   experience   has   shown   that   in   tubercular 

disease  of  the  eye  the  exhibition   of  small  doses  of   tuberculin, 

such  as  we  are  now  in  the  habit  of  giving,  has  never  produced 

any  harmful  result  on  the  patient's  general  health,   whereas,   in 

a     number    of    cases    after    enucleation,     death    occurred    from 

meningitis.     Time  alone  will  decide  whether  by  this  treatment 

all  tubercular  eyes  can  be  saved ;  the  disease  is  so  rare  that  the 

clinical  material  of  a  single  individual   is  not  enough  to   make 

certain.     But  even  if  only  a  considerable  proportion  are  saved — = 

and    my    results    are    sufficient    to    establish    this — we    can    still 

chronicle   a   refreshing   advance    in   therapeutics,    made   possible 

for  us  by  the  genius  of  Robert  Koch  alone." 

In    1905    v.    Hippel    records   twelve   further   successful   cases 

by  his  method,  and  again  recommends  the  treatment  with  small 

doses  over  a  long  period  of  time. 

0  .       ...  r   Among  the  latest  reports  of  the  success  of 

Superior  Value  of  ,•      •  ,     .        ,     , 

tuberculin    in    tuberculosis    of   the   eye    are 

y  those  of  Davids  [270]   from  the  Gottingen 

hmulsion.  University    Ophthalmic    Clinic,    emphasiz- 

ing the  superior  curative  effect  of  bacillary  emulsion,  which 
he  considers  specially  protective  against  relapses.  The  prepara- 
tion did  not  fail  in  any  of  the  ten  cases  treated.  In  various 
forms  of  keratitis  the  cornea  cleared  noticeably.  In  all  cases 
of  tuberculosis  of  the  iris  the  tubercles  disappeared  quickly, 
even  when  at  first  they  had  shown  a  tendency  to  multiply  and 
increase.  In  the  same  way  pupillary  exudation  subsided  in  a 
striking  manner,  the  vitreous  humour  cleared  and  sclerotic 
tubercles  subsided.  Finally  bacillary  emulsion  was  also  effective 
in  conjunctival  tuberculosis. 

In  other  quarters,  too,  bacillary  emulsion  is  preferred.  Thus 
Scheuermann  [271],  from  striking  results  in  twenty-five  cases  in 
the  Charlotte  Sanatorium  for  Diseases  of  the  Eye  in  Stuttgart, 
cannot  recommend  it  too  highly.  The  most  striking  cure  was 
that  of  two  solitary  tubercles  of  the  retina,  choroid  membrane, 
and  optic  disc,  which  would  certainly  have  resulted  in  loss  of 
the  eye;  with  the  exception  of  a  slighj,  diminution  of  the  field 
of  vision,  the  eye  became  quite  normal. 

Bacillary  emulsion  proved  just  as  successful,  according  to 
Pick,  in  a  case  of  severe  tuberculosis  of  the  eyeball,  which  had 
attacked  extensively  the  conjunctiva  of  the  ball,  the  cornea,  the 
iris  and  the  episclerotic,  and  had  led  to  clouding  of  the  vitreous 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  255 

humour  and  severe  neuritis  optica.  Uhthoff  recommends  it  in 
specific  tubercular  growths  in  the  iris  and  uveal  tract ;  Jung  gives 
it  an  unreserved  recommendation.  Horniker  completely  cured  a 
very  advanced  case  of  tuberculosis  of  the  iris. 

Schnaudigel  [272]  treated  ninety-five  cases 
Schnaudigel.  Qf  t^e  most  diverse  forms  of  tuberculosis 
of  the  eye  with  good,  often  with  brilliant  results.  The  cases 
were  divided  among  the  different  parts  of  the  eye  in  the  following 
way:  Phlyctenular  keratitis,  16;  severe  keratitis  with  ulceration, 
pannus  and  suppurating  infiltrations,  30;  quite  torpid,  recurrent 
inflammation  of  the  cornea  in  childhood  and  in  the  second 
decennium,  3  ;  serous  iritis,  6 ;  creeping  plastic  iritis  with  disease 
of  the  uvea  and  keratosclerosis,  27  ;  uveitis  with  detachment  of 
retina,  2;  central  and  disseminated  choroiditis,  4;  diffuse 
choroiditis,  2 ;  episcleritis,  2 ;  optic  neuritis,  1  ;  retrobulbar 
neuritis  with  affection  of  the  sphenoidal  sinus,  2. 

v.      Herrenschwand's     [273]      results      are 
v.  Herrenschwand.    equally     favourable.        He      secured      far„ 

reaching  improvement,  for  the  most  part,  even  cure  in  twelve 
cases  of  parenchymatous  keratitis,  thirteen  of  phlyctenular  con- 
junctivitis of  the  cornea;  one  of  scleritis ;  seven  of  iritis,  and  six 
of  disseminated  choroiditis. 

Tuselius   gives   details   of   thirteen    cases   of 

iJ  1  J  ^P  1 1  I  J  ^ 

active   ocular  tuberculosis    (iritis,    keratitis, 

choroiditis,  &c),  all  of  which  were  cured. 

0  .       1.0  One     of     the     latest     publications     which 

Schoeler  s  Success    .  .  r  .    , 

.  deserves  mention   on  account   of   the   large 

material  of  170  cases,  is  that  of  F. 
Old  Tuberculin.  Schoeler  [124],  of  the  Schoeler  Ophthalmic 
Clinic,  in  Berlin.  It  is  specially  noteworthy  that  the  results  are 
achieved  with  old  tuberculin.  Schoeler  reports  on  the  remark- 
able effect  of  tuberculin  in  superficial  and  parenchymatous 
keratitis,  iritis,  choroiditis,  scleritis,  and  episcleritis,  vitreous 
opacity  and  recurrent  vitreous  haemorrhage  on  a  tubercular 
basis,  also  in  retrobulbar  neuritis  of  a  tubercular  nature.  His 
experiences  may  be  summarized  as  follows  :  The  use  of  old 
tuberculin  is  strongly  to  be  advised  in  suitable  cases,  in  con- 
junction with  the  other  known  remedies.  It  aids  them  and  in- 
creases the  receptivity  and  tolerance  of  the  eves  for  other 
remedies.  In  some  cases  it  has  been  effective  in  saving  the  eye. 
The  dosage  must  be  chosen  so  as  to  cause  slight  increases  of 
temperature  of  a  few  tenths  of  a  degree.  Local  reactions  always 
pass  off  harmlessly  without  leaving  any  trouble  behind.  The 
tuberculin  cure  is  a  lengthy  one  and  must  be  continued  till  no 
signs  of  disease  are  present,  or  until  even  with  a  rapid  increase 


256  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

of  the  dose  no  rise  in  temperature  occurs.  Maximum  dose, 
500  c.mm.  Relapses  sometimes  occur,  but  less  frequently  than 
without  tuberculin. 

Heine    [120]    bases    his   judgment    on    125 
Heme"  cases   in   which   there   was   unmistakably   a 

favourable  effect  in  one  half,  absent  in  the  other  half.  There 
were  eleven  relapses  after  completion  of  treatment,  three  during 
suspension  of  treatment.  The  earlier  the  cure  was  commenced, 
the  better  was  the  result.  On  the  ground  of  the  success  attained 
and  the  improvement  in  body-weight  and  the  subjective  condi- 
tion of  the  patients,  he  considers  tuberculin  a  very  efficacious 
remedy. 

Gerok's    results   in    twenty-five   cases   were 
satisfactory    and    some    quite    surprisingly 
U  uberculin.     successful.     Ten  cases  of  iridocyclitis  gave 

uniformly  satisfactory  results.  Also  cases  of  scleritis,  iritis  and 
choroiditis  disseminata  were  favourably  influenced,  keratitis 
parenchymatosa  less.  A  case  of  cerebral  tumour  with  choked 
optic  disc  was  healed  and  remained  so  during  three  years' 
observation.  Old  tuberculin  proved  the  best  preparation,  very 
small  doses  being  used  and  febrile  and  local  reactions  avoided 
as  far  as  possible. 

Recently  Leber  has  also  expressed  his 
opinion  that  old  tuberculin  is  equal  to  the 
bacillary  preparations  in  therapeutic  efficiency,  that  its  use  has 
a  theoretical  foundation  in  the  local  character  of  ocular  diseases, 
that  it  is  less  likely  to  cause  toxic  injury  to  the  eye  and  deserves 
preference  as  it  is  easier  to  apply. 

Weeks,  as  a  result  of  inquiries  of  102  North 

VV  £*£*  K  ^ 

American  oculists,  informed  the  Inter- 
national Medical  Congress  in  Budapest,  in  1909,  that  the  results 
obtained  in  tuberculosis  of  the  eye  by  tuberculin  were  described 
on  all  sides  as  satisfactory.  The  preparations  used  were  original 
old  tuberculin,  new  tuberculin  TR,  and  best  of  all,  bacillary 
emulsion,  according  to  v.  Hippel's  prescription. 

■      .     ,  The     special     recommendation     by     Junius 

_,  ...  of  Beraneck's  tuberculin  in  tuberculosis  of 

Recommendation     .,  ,         ,  ,        .,  ..     , 

,  the     eye,      based     on      purely     theoretical 

OT  BeranecK  s        grounds,   without  any  personal  experience, 

Tuberculin.  seems  to  us  not  only  unjustified,   but  also 

superfluous,  at  the  present  time,   in  view  of  the  brilliant  results 

with    Koch's    preparations    of    tuberculin    and    the    universally 

accepted  and  thoroughly  tested  method  of  v.  Hippel.     The  value 

of  Beraneck's  tuberculin  in  itself  is  not  disputed.     According  to 

Fleischer,  it  has  been  used  amongst  other  preparations  and,  com- 


THE  SPECIFIC  TREATMENT  OF  TUBERCULOSIS        257 

bined  with  clinical  treatment,  used  for  a  sufficient  length  of  time 
and  with  great  care,  gives  results  equally  as  good  as  other  tuber- 
culins. 

.  ..  With  Marmorek's  serum  Ullmann  obtained 

Use  of  Mar-  „  ,      .  ,  , 

excellent  results  in  twenty  cases  ot  scrotu- 

morek's  Serum.  ]ous  disease  0f  ^  cornea,  mostly  in 
children.  He  emphasizes  the  necessity  of  early  treatment. 
Verrey  also  had  a  favourable  result  from  the  rectal  adminis- 
tration of  serum  in  a  patient  suffering  from  corneal  tuberculosis 
with  pannus,  also  from  tuberculosis  of  the  bones.  The  value  of 
the  serum  is  also  confirmed  by  Schwartz,  disputed  by  Bock. 

7.— TUBERCULOSIS  OF  THE  EAR. 

In  otological  text-books  the  therapeutic  use  of  tuberculin  in 
tubercular  affections  of  the  ear  is  either  not  mentioned  at  all  or 
adversely  criticized,  the  reason  probably  being  that  tuberculin  has 
been  very  little  used  in  tuberculosis  of  the  ear.  All  the  more 
valuable,  therefore,  are  the  experiences  of  Voss  [275],  who,  at  the 
Scientific  Congress  in  the  Municipal  Hospital  at  Frankfurt-on- 
the-Maine,  introduced  a  patient  who  had  been  cured  by  systematic 
injections  of  bacillary  emulsion  of  a  chronic  suppuration  of  the 
middle  ear  on  both  sides,  with  serious  defects  in  the  tympanic 
membrane  and  an  infiltration  on  the  left  side  with  fibrinous  exuda- 
tion in  the  region  of  the  promontory ;  other  methods  had  long 
been  tried  without  avail.  Voss  considers  such  cases  speciallv 
suited  for  specific  treatment,  and  thinks  that  chronic  suppurations 
of  the  middle  ear  can  be  cured  by  means  of  tuberculin.  Cipes 
records  another  case  of  cure  of  tubercular  disease  of  both  ears  by 
combined  tuberculin  and  local  treatment. 

In  acute  tuberculosis  of  the  middle  ear  and  of  the  mastoid 
process  he  would,  however,  advise  the  greatest  caution,  in  con- 
trast to  Lebram,  who  has  observed  a  curative  effect  from  tuber- 
culin even  in  these  acute  processes. 

8.— TUBERCULOSIS  OF  THE  SKIN. 

History  of  Lupus     The  treatment   of  tuberculosis   of  the   skin 
_    '  and  especially  of  lupus  has  undergone  many 

vicissitudes.  As  long  as  it  belonged  to  the 
sphere  of  internal  medicine  the  results  were  by  no  means  satis- 
factory. With  the  rise  of  dermatology  to  a  separate  place,  pro- 
gress began.  The  next  stage,  a  transition  to  the  surgical,  was 
to  destroy  lupus  nodules  by  scarifying  or  by  means  of  the  electric 
cautery  or  the  sharp  spoon.     The  surgeon  finally  set  himself  the 

17 


258  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

task  of  the  radical  removal  of  the  diseased  parts.  When  the 
cases  chosen  are  suitable,  excellent  results  are  attained  in  this 
way,  but  the  method  has  its  limitations,  as,  for  instance,  in  lupus 
of  the  mucous  surfaces,  especially  of  the  nose,  and  in  disease  pro- 
cesses not  accessible  to  complete  extirpation  ;  and,  finally,  where 
the  lack  of  bodily  strength  bars  the  way.  A  further  advance  in 
the  treatment  of  lupus  was  made  by  the  introduction  of  Finsen's 
method,  by  Rontgen  rays,  and  radium.  To  radium  treatment 
the  objection  has  been  raised  that  it  is  difficult  to  limit  the  action 
of  the  rays.  The  Finsen  reaction  is  easy  to  estimate,  but  the 
deeper  the  lupus  tissue  extends  into  the  subcutaneous  layer  and 
the  greater  its  extent  the  less  is  the  prospect  of  success,  and  this 
is  still  further  compromised  by  the  presence  of  extensive  scarring 
from  previous  unsuitable  treatment.  In  extensive  superficial 
processes,  and  those  combined  with  disease  of  a  mucous  surface, 
Hollander's  hot  air  treatment  has  shown  itself  of  service.  Of  the 
latest  methods  of  treatment — the  internal  exhibition  of  sodium 
iodide  and  the  simultaneous  use  of  ozone  or  hydrogen  peroxide 
(Pfannenstill)  and  Nagelschmidt's  diathermal  treatment — there 
are  at  present  insufficient  records ;  to  all  appearances  they  are 
further  advances. 

.         .   ^  .In  addition  to  the  local  treatment  of  tuber- 

Local  and   General        ,        -,  .        rr  ,  , 

cular  skin  affections,  the  general  treatment 

of  the  organism  as  a  whole  plays  a  con- 
siderable part.  Tuberculin  is  an  accessory  to  general  ■  and 
etiological-specific  treatment.  Even  in  the  first  tuberculin  era 
striking  cures  were  recorded ;  but  with  the  modern  advances  in 
dermatology,  tuberculin  was  undeservedly  thrown  into  the  back- 
ground, whence  it  is  only  recently  emerging  to  be  increasingly 
used  in  the  most  varied  forms  of  tuberculosis  of  the  skin  and 
mucous  membrane. 

Lichen  Scrofulo-     Great    success    has    attended    the    specific 

A         ~     .         treatment   of   lichen   scrofulosorum,    Kling- 
sorum,  Acne  Cachec-      ....  .      _,      .       _  ..'„..  * 

_  muller  at  the  breslau  Dermatological  Clinic 

ticorum,  Scrofu  o-  .•  ^r  4.1.  j 

'  reporting  cures.       Many  authors  record  a 

derma  and  try-      favourable  influence  on  acne  cacheetioorum 

thema  Induratum.    and    some    a    cure.      Thorner's    results    in 

scrofuloderma  are  satisfactory.     Thibierge  and  "Weissenbach,   in 

ambulant  practice,  cured  five  cases  of  ervthema  induratum  with 

increasing   doses   of   various   tuberculins   without    any    accessory 

general  treatment.     Whitfield,  Jeanselme,  and  Choralier  confirm 

its  curative  effect. 

There  are   naturally  many  more  records  of 

P     "  experiences  in  the  treatment  of  lupus.     Its 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  259 

many-sided  nature  explains  the  fact  that  the  results  in  all  its 
forms  and  in  all  cases  are  not  equally  favourable.  Between  the 
use  of  old  and  new  tuberculin  no  essential  differences  have  been 
proved.  From  the  very  rich  literature  of  the  subject  we  can  only 
quote  the  names  of  some  who  have  recorded  improvements  follow- 
ing specific  treatment  :  Adler,  Balzer,  Beck,  Bieck,  Bukowsky, 
Bussenius,  Brocq,  Browker,  Campana,  Cossmann,  Crocker, 
Darier,  Delbanco,  Doutrelepont,  Dressier,  Faure,  Gerber,  Gross, 
Gunson,  Heermann,  Heron,  Jadassohn,  Jesionek,  Kernig,  Krzysz- 
talowicz,  Lassar,  Leredde,  Lesser,  Little,  Litzner,  Mayer,  May- 
nard,  Medowikow,  Morris,  Pernet,  Porges,  Prang,  Roberts, 
Seeligmann,   Sternthal,   Walsch,   Western,   and  Wright. 

.  —   ,  ,.       Many  authors  have  tried  the  local  applica- 

Local  Tuberculin  J  r     ,  ,       ,  ...  .         ,  . 

tion  of  old  tuberculin   in  various  forms  in 

Application.  the  treatment  of  lupus.     Blaschko,  Crocker 

and  others  have  injected  tuberculin  dilutions  into  the  lupoid  tissue 
to  promote  local  reactions  with  small  doses  and  avoid  general 
reactions.  On  the  same  principle  Verge  recommended  a  5  per 
cent,  tuberculin  ointment.  Unna  successfully  used  inunction  of 
a  "tuberculin  soap"  (sapo  unguinosus  with  5  to  20  per  cent, 
tuberculin)  for  lupus,  with  the  idea  of  setting  free  autotuberculin 
by  massage,  and  rendering  it  active.  Blaschko  and  Hallopeau 
used  tuberculin  fomentations.  Neumann  scarified  the  lupoid  sur- 
face and  impregnated  it  with  tuberculin.  Ohler  recommends  the 
painting  of  tubercular  ulcerations  with  tuberculin,  by  which 
means  Schnitzler  also  observed  disintegration  and  healing  in 
tumours  of  the  nasopharynx.  Nagelschmidt  has  employed  the 
production  of  a  v.  Pirquet  papule  in  the  local  focus  when  ulcera- 
tion varying  in  extent  and  depth  almost  always  took  place  and  in 
some  cases  led  to  clinical  healing  of  the  tubercular  skin  focus 
although  only  within  a  few  millimetres  radius. 

Subcutaneous       A11    these    methods    have    found    but    few 
.    .  followers.     In  tuberculin  treatment  of  lupus, 

J  as  elsewhere,  the  subcutaneous  method  has 

Preferable.  proved  its  superiority  as  the  great  majority 

of  the  above  authors  bear  witness.     Of  other  noteworthy  results 

the  following  must  be  mentioned  :   Raw  has  treated  100  cases  of 

lupus  with  old  tuberculin,   the  great  majority  of  which  showed 

improvement.     Jochmann's  reports  are  also  favourable. 

.  "  Patients,    who    had    been    treated    locallv 

Jochmann.  .,,  ,          .  , 

with   every   remedy   without   success,    made 

good  progress  under  treatment  with  tuberculin.     In  other  cases 

we  had  the  impression   that  after  distinct  improvement  at  first, 

later   a   standstill    occurred.       Tuberculin    treatment    is    specially 


260  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

called  for  in  cases  in  which  other  local  remedies — pyrogallic  acid, 
the  Finsen  treatment,  or  Rontgen  rays — cannot  penetrate,  such 
as  processes  which  attack  the  mucous  membrane  of  the  nose." 
In  his  statement  at  the  third  session  of  the  lupus  section  of  the 
German  Central  Committee  for  the  Preven- 
Wicnmann.  tjon  Qf  consumption,  Wichmann  describes 

tuberculin  as  follows  :  "  Although  no  sovereign  remedy,  it  is  a 
very  valuable  accessory  and  often  an  indispensable  factor  in  the 
treatment  of  lupus." 

^.     .         r  As    we    have    alreadv    mentioned,    no    one 

Choice  of  -  ' 

tuberculin   has   shown   any  marked  supen- 
Tubercuhn.  ority  in  the  treatment  0f  t^e  disease.     Sahli 

here,  too,  prefers  Beraneck's  tuberculin,  Rosenbach  his  own 
preparation.  The  authors  have  published  reports  of  various 
cases  successfully  treated  with  old,  new  and  bovine  tuberculins. 
The  efficacy  of  bovine  preparations  is  specially  emphasized  by 
some  authors  who  are  inclined  to  draw  conclusions  from  their 
action  as  to  the  etiology  of  lupus ;  thus  Jochmann  and  Mollers 
recommend  bovine  tuberculin  in  all  cases  where  the  human 
preparation  has  no  effect. 

Combination  of      ^e  existin§"  results  suffice,  at  any  rate,  to 

-r   ,  ,.  ...       direct  further  attention  to  the  treatment  of 

Tuberculin    with     .  ^ 

.m     ,  „    lupus     with     tuberculin.        1  he     sovereign 

other  Methods  of    „     ,  ,.       (       ,  , 

modern    remedies    for    lupus,    as    we    have 

reatment.  seen,  have  their  contra-indications  and  limi- 

tations, especially  in  lupus  of  the  mucous  membrane.  But  there 
is  no  reason  why  tuberculin  should  fail  here.  We  have  empha- 
sized this  for  years,  and  are  gratified  to  find  that  Wichmann  has 
recently  recommended  tuberculin  as  the  most  valuable  remedy  for 
lupus  of  the  mucous  membrane.  Reports  (for  example  from  A. 
Neisser  and  F.  Becker)  exist  which  show  that  lupus  of  the  mucous 
membrane  of  the  nose,  mouth,  and  throat  were  healed  more 
rapidly  and  easily  than  the  lupus  of  the  facial  skin,  present  at  the 
same  time.  B.  Frankel,  too,  a  short  time  ago  gave  a  detailed 
•description  of  the  cure  of  a  case  of  extensive  lupus  of  the  gums 
with  a  small  primary  focus  in  the  nasal  septum  by  large  tuber- 
culin doses.  A  careful  study  of  the  experience  of  the  last  decade 
will  inevitably  lead  to  assuring  the  place  of  tuberculin  in  the  treat- 
ment of  lupus  in  combination  with  the  other  well-proved 
remedies.  Senger  considers  that  no  other  treatment  has  so  good 
an  effect  on  lupus  as  the  inunction  of  tuberculin  ointment  with 
vasenol  in  3  to  10  per  cent,  concentration,  in  conjunction  with 
Rontgen  rays.  Further,  Wichmann,  who  has  recorded  lasting 
cures  of  severe  cases  of  lupus  of  skin  and  mucous  membrane,  has 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  26 1 

observed  that  tuberculin  only  displays  its  full  curative  value  when 
the  diseased  tissue  is  previously  rendered  plethoric,  e.g.,  by  weak 
Rontgen-ray  treatment.  And  according  to  the  experience  of  the 
Rostock  Dermatological  Clinic,  old  tuberculin,  in  combination 
with  other  methods,  has  proved  its  value,  especially  in  open 
lupus,  in  destroying  the  tubercular  tissue. 

"  The  exciting  cause  of  the  disease  seems  to  be  enticed  from  the  body 
and  given  out  by  exudation,  and  is  then  destroyed  by  pyrogallic  acid  " 
(Wolters). 

The  justice  of  our  claim  has  been  lately  acknowledged  by 
dermatologists,  for  instance  by  A.  Neisser,  Doutrelepont,  Scholtz, 
Blaschko  and  Wichmann.  A.  Neisser,  in  contradistinction  to 
Doutrelepont,  has  not  observed  pure  tuberculin  cures,  but  he  con- 
siders tuberculin  quite  an  indispensable  aid  in  the  treatment  of 
lupus. 

"  Especially  cases  with  large,  swollen  infiltrations  and  all  infiltration 
of  the  mucous  membrane  of  the  mouth  are  treated  by  us  with  tuberculin, 
always  by  slowly  increasing  doses,  but  large  enough  to  produce  local 
reactions.  In  this  way  thick,  swollen  infiltrations  become  flat  and  smooth 
surfaces,  in  which  the  lupus  foci  are  easily  recognizable  and  amenable  to 
further  treatment  with  light  "     (A.   Neisser). 

We  need  the  assistance  of  tuberculin  in  the  treatment  of  lupus 

all  the  more  as  in  a  fairly  high  percentage  of  cases  tuberculosis 

of  the  skin   is  combined  with  other  internal  tubercular  disease, 

especially  of  the  lung.       And  precisely  on  this  account  specific 

treatment  is  in  place. 

,  i(       Heuck  also,   who  confirms  the  good  effect 
Importance  of  the     c    ^  ,  '  ,  ,      .  , 

r  of     tuberculin    on    lupus,     emphasizes    the 

er      in  importance    of    the    tuberculin    reaction    in 

Reaction.  recognizing  the  limits  of  the  diseased  and 

healthy    tissue.     These    experiences    agree    with    those    of    A. 

Neisser,  who  for  years  has  utilized  the  local  tuberculin  reaction 

both  for  purposes  of  excision  and  for  subsequent  testing  of  the 

cure. 


9.— TUBERCULOSIS  OF  GLANDS,   BONE,  AND  JOINTS. 

~  x.  Tuberculin  has  been  but  little  tried  in  the 

Operative  .         r  ...  ,     .      TT., 

.  great  region  of  surgical  tuberculosis.    When 

removal  of  the  disease  by  surgical  measures 

Treatment.  js    possible,    radical    operation    has    always 

obtained  the  preference.     But  recently  there  has  been  a  reversion 

to  more  conservative  treatment,  due  in  no  small  degree  to  Bier's 

pioneer  work.     But  hyperemia  also  plays  the  principal  role  as 


262  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

curative  agent  in  tuberculin,  and  the  two  methods  have  this  in 
common  in  their  fundamental  action.  We  here  stand  only  at  the 
beginning  of  things,  but,  if  the  signs  do  not  deceive,  conservative 
therapy  in  combination  with  specific  treatment  is  destined  in- 
creasingly to  limit  surgical  measures,  to  assist  in  many  cases, 
and  in  some  to  replace  them.  This  view,  which  has  always  been 
emphasized  by  the  authors,  has  lately  been  accepted  by  surgeons 
of  authority:  Wilms  [127],  who  has  observed  the  greatest  suc- 
cesses in  the  specific  treatment  of  the  fungoid  form  of  surgical 
tuberculosis,  considers  the  tuberculin  cure  not  only  appropriate 
for  these  cases,  but  absolutely  essential,  as  a  means  of  strengthen- 
ing the  body  against  the  tubercular  infection  and  especially  of 
protecting  it  against  relapse  after  removal  of  the  fungoid  focus. 
"  The  surgeon  who  rejects  tuberculin  therapy  loses  thereby  a 
very  efficacious  remedy  which  I  consider  more  valuable  than 
iodoform,  glycerine,  stasis,  &c,  and  which  can  only  be  compared 
with  Rontgen  treatment.  I  am  convinced  that  the  conservative 
treatment  of  tuberculosis,  in  distinction  to  the  surgical  methods 
still  generally  practised,  will  gain  ground  year  by  year."  At  the 
Karlsruhe  Scientific  Association,  in  191 1,  at  which  Wilms  put 
forward  this  standpoint,  Czerny  also  declared  his  faith  in  tuber- 
culin. 

It  is  well  known  that  a  large  percentage  of  cases  of  "surgical 
tuberculosis,  after  being  cured  of  their  local  affection,  ultimately 
die  of  pulmonary  or  other  internal  tubercular  disease.  And  there 
can  no  longer  be  any  doubt  that  a  systematic  testing  of  the 
susceptibility  to  tuberculin,  and  if  necessary  a  course  of  treatment 
with  it,  will  immensely  improve  the  results  in  the  whole  group  of 
surgical  tuberculosis ;  and  not  merely  this,  but  prevent  the  out- 
break later  of  a  focus  of  tuberculosis  localized  in  some  other  part, 
which,  after  long  being  latent,  might  sooner  or  later  lead  to  a 
fatal  attack.  We  owe  it  specially  to  Kraemer  to  have  repeatedly 
and  urgently  emphasized  this  and  established  its  correctness  be- 
yond dispute. 

_,  In       cases       of       glandular       tuberculosis, 

Petruschky,  where  the  disease  was  closed, 
in  Glandular  obtained  100  per  cent,  of  cures  with  old 
Tuberculosis.  tuberculin.  Kramer  reports  just  as  favour- 
ably ;  he  considers  tuberculin  treatment  in  the  case  of  children 
not  only  as  the  most  important  curative  agent  in  glandular  tuber- 
culosis, which  is  usually  in  the  foreground,  but  also  for  the 
extermination  of  tuberculosis  in  general.  Tuberculosis  of  the 
bronchial  glands,  too,  in  children  and  adults,  is,  according  to  his 
experience,  a  specially  favourable  object  for  tuberculin  treatment, 
all  the  more  because  a  large  number  of  forms  of  manifest  tuber- 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  263 

culosis  proceed  from  it.  v.  Starck  also  observed  after  the  use  of 
old  tuberculin  in  tuberculosis  of  the  bronchial  glands  of  children 
a  strikingly  good  subjective  condition,  which  was  always  followed 
by  objective  improvement.  Rohmer  proved  a  tendency  to 
anatomical  healing  in  the  form  of  proliferation  of  the  connective 
tissue  and  encapsulation  of  the  bronchial  glands  in  three  children 
under  2  years  of  age,  who  died  of  other  complications. 

Peiper,  at  one  time  an  opponent  of  specific  treatment,  has 
observed  very  satisfactory  results  in  the  glandular  tuberculosis  of 
children  from  the  employment  of  minimal  doses  of  old  tuberculin. 
The  same  favourable  opinion  is  held  by  Jochmann,  Scherer, 
Aronade,  Ullmann,  Dumas,  Lawson,  Raw,  Stoll,  K.  and  S. 
v.  Ruck,  Hawes,  and  Floyd.  Latham  reports  prompt  results  in 
anemic  and  febrile  children  with  glandular  tuberculosis;  he 
emphasizes  the  necessity  of  lengthy  treatment,  which  must  be 
prolonged  after  improvement  has  taken  place.  Heubner  states 
that  the  immediate  result  of  careful  tuberculin  treatment  in 
glandular  tuberculosis  of  young  children  is  unmistakable  as  far 
as  the  improvement  of  the  general  condition  and  the  scrofulous 
symptoms  are  concerned.  Baginsky  also  recently  recommended 
careful  treatment  with  tuberculin.  Pogue  obtained  very  satis- 
factory results  in  ten  cases  of  glandular  tuberculosis  with  the 
formation  of  fistulas.  Guinard,  in  his  cases,  always  observed 
softening  and  breaking  down  of  the  glands. 

Dautwiz  [276]  made  an  important  contribu- 
Dautwiz.  tjQn  tQ  tjie  curative  influence  of  tuberculin 

in  latent  endothoracic  glandular  tuberculosis  in  children.  Accord- 
ing to  his  wide  experience  it  undoubtedly  effects  more  in  con- 
junction with  hygienic-dietetic  treatment  than  the  latter  does 
alone,  more  also  than  the  sea-bath  treatment  (previously  the  most 
efficacious),  even  when  this  is  repeated  every  year  for  three  to 
four  months.  The  superiority  of  tuberculin  treatment  is  seen 
in  the  children  recovering  more  quickly,  more  regularly  and 
without  relapses,  losing  their  subfebrile  and  febrile  temperature 
as  well  as  the  sternocostal  and  spinal  tenderness,  and  proving 
themselves  much  more  capable  of  resistance  on  their  return  to 
less  favourable  conditions  of  life.  Dautwiz  considers  the  most 
important  point  is  the  proof  of  the  effect  of  tuberculin  treatment 
on  the  endothoracic  glands ;  he  considers  the  principal  effect  of 
tuberculin  to  lie  in  the  hvperasmia  and  hyperleucocytosis  of  the 
glands  and  their  surroundings  resulting  finally  in  encapsulation, 
capsular  thickening  and  closing  of  the  vasa  efferentia.  He  has 
been  able  regularly  to  prove  this  fibrous  thickening  of  the  capsule 
and  the  more  or  less  complete  calcification  of  its  contents  in  com- 
parative Rontgen  photographs  by  more  distinct  isolation,  greater 


264  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

plasticity  and  sharper  definition  of  the  edges.     Bauer  and  Engel 

[100]    express  their  full   agreement  with  this  conception   of  the 

tuberculin  cure  of  glandular  tuberculosis  as  a  whole;  they  have 

never  seen   softening   of   the   glands,    even    when   these   were   so 

superficial  that  changes  must  have  attracted  attention.     Dautwiz 

only  uses  Koch's  old  tuberculin  for  strong  children  when   it  is 

borne  without  reaction  ;  otherwise  he  prefers  the  milder  Beraneck 

tuberculin,  according  to  Sahli's  principles. 

Jochmann   [171]    reports  as  follows  on   the 

Jochmann.  excellent  results  in  tuberculosis  of  the  glands 

in    children:    "Children    with    scrofulous    taint,    thickly    swollen 

glands  in  the  neck  and  scrofulous  eczema,  also  those  with  swelling 

of     the    bronchial     glands,     shown     in     Rontgen     photographs, 

flourished  under  tubercular  treatment  and  gained  continuously  in 

weight.     The    scrofulous    appearance    improved,    the    glandular 

swelling  diminished  and  disappeared.     These  changes  were  all 

the  more  striking  as  they  were  largely  children  who  had  formerly 

been  treated  with  the  usual  symptomatic  remedies  without  success. 

We  used,  besides  old  tuberculin,  TR." 

,  We  have  ourselves  often  observed  that  the 

Authors  ,       ...  .  ,  ,     .,  r  •     1 

familiar    picture    of    the    row    of    cervical 

Experience.  glands,    like  a  string  of  beads  the  size  of 

haricots  or  larger,  disappearing  without  leaving  any  trace  under 
treatment  with  Koch's  preparations,  or  decreasing  till  they 
become  hard,  fibrous  cords.  If  softening  has  really  occurred  in 
larger  glands  with  central  caseation,  no  longer  capable  of 
absorption,  assistance  is  obtained  by  simple  puncture  or  a  small 
incision  and  suction.  Rarely  is  total  extirpation  necessary. 
Wilms  [127]  even  warns  for  special  forethought  in  removing 
these  protective  organs  in  youth;  "but  when  caseation  and 
suppuration  render  operation  necessary,  then  the  fortification  of 
the  body  against  the  infection,  to-day  both  possible  and  appro- 
priate, must  not  be  neglected."  Hewlett  takes  the  same  view  in 
recommending  periodical  tuberculin  treatment  after  removal  of 
glands  to  attain  immunity. 

Krause  has  obtained  surprising  results,  both  in  small 
hardened  glands  and  also  in  those  which  had  already  begun  to 
suppurate  and  had  led  to  the  formation  of  fistulas.  Schnaudigel 
reports  similarly. 

W.  Neumann  [277]  observed  under  TR,  BE  and  tuber- 
culinum  purum,  tubercular  lymphatic  glands  with  and  without 
suppuration,  with  and  without  the  formation  of  fistula?,  heal 
quite  smoothly  even  with  the  complication  of  severe  pulmonary 
tuberculosis.     The  healing  was  often  proved  anatomically. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  265 

Reunert  cured  with  TR  a  case  of  tonsillar 
Various  Tuberculins  tuberculosis     and     observed     swellings     of 

Employed.  glands    and    spleen    diminish    during    the 

treatment.  In  a  case  of  tuberculosis  of  the  iris,  accompanied  by 
a  progressive  tubercular  infection  of  the  lymphatic  system  re- 
sembling pseudo-leukaemia,  the  disease  was  arrested.  Sahli  uses 
Beraneck's  tuberculin  with  success,  Wright  TR,  F.  Krause,  M. 
Elsasser,  Butler  Harris,  Turton,  and  Parkin  bacillary  emulsion, 
Rosenbach  his  own  tuberculin.  Klebs  reports  the  cure  of  100  per 
cent,  of  cases  of  tuberculosis  of  the  lymphatic  glands  with 
tuberculocidin  and  selenin.  Jacobs  also  reports  complete  cures 
with  his  preparations,  which  Lespinne  confirms  from  his  own 
experience. 

Marmorek's  serum  also  has  been  employed 
Use  of  Serum.       with  success  by  Wohlberg,   Ullmann,   van 

Huellen,   F.  A.   Elsasser,   and  Rover  in  scrofula  and  glandular 

tuberculosis ;  they  saw  remarkable  improvement  and  even  cure. 

Preleitner's  experiments  in  glandular  tuberculosis  of  children  were 

quite  negative,  those  of  Szurek  unsatisfactory. 

In  Tuberculosis  of  °f  old   tuberculin    in   tubercular  disease  of 

,_,  ,    .    .   s       bones  and  joints  favourable  report  is  made 

Bones  and  Joints.    .         TT11        J         T  ..,,  a  .         n 

by     Ullmann,     Ludke,     Aronade,     Pogue, 

Use   of  Medowikow,      Jones,      Smith      (thirty-four 

Old  Tuberculin.  cases),  Cathcart,  Macleod,  Loewenstein, 
and  others.  At  the  meeting  of  the  Research  Society,  in  1908, 
Schlossmann  and  Engel  reported  good  results  from  old  tuber- 
culin in  tubercular  diseases  of  the  bones  and  joints  in  young- 
people,  giving  demonstrations  with  Rontgen  photographs ;  they 
brought  about  a  complete  anatomical  cure  in  two  cases  of  spina 
ventosa,  one  case  of  tubercular  knee-joint  and  one  case  of  tuber- 
culosis of  the  ulna  with  abscess  formation  and  necrosis.  In  the 
larger  treatise  already  quoted  Engel  completes  his  report  on  the 
most  favourable  results  of  tuberculin  at  the  Dusseldorf  Academic 
Clinic  for  Children  in  cases  of  tuberculosis  of  the  bones  and 
joints.  A  typical  case  of  caries  of  the  ribs  was  cured  by 
Deterding  and  de  Groot  with  twenty-three  injections  of  tuber- 
culin, one  case  by  Roebroeck  with  Denvs'  tuberculin.  This 
tuberculin  has  also  received  Westerveld's  recommendation  for 
the  treatment  of  surgical  tuberculosis.  Ormond  cured  four 
severe  cases  of  tubercular  periostitis  with   tuberculin. 

,  Elsewhere,  too,  old  tuberculin  has  recentlv 

Lenzmann  ;  ,  ,  .  ,      .  - 

been  used  more  frequently  in  surgery,   tor 

instance,    for   tubercular   ulcers   and   severe 

granulating  fistula?.  Thus  Lenzmann  [278] 


Treatment. 


266  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

has  seen  the  finest  results  in  soft  tubercular  granulations,  which 
had  been  several  times  removed  without  success  and  always  pro- 
liferated again.  According  to  Lenzmann,  if  the  shedding  of  the 
tubercular  tissue  presents  no  obstacle,  one  can  proceed  with 
rapidly  increasing  doses,  provided  that  there  is  no  complicating 
tuberculosis  of  an  internal  organ,  especially  of  the  lung;  should 
there  be  a  complication  the  tuberculin  treatment  is  regulated  by  it 
and  great  caution  must  be  used.  In  suitable  cases,  especially  in 
tuberculosis  of  the  carpus  and  tarsus,  he  recommends  intrafocal 
injections;  the  tuberculin  is  injected  into  the  tubercular  focus 
along  with  liquid  paraffin  and  is  used  to  retain  the  tuberculin 
longer  in  the  focus.     He  has  had  very  satisfactory  results. 

In  Tilman's  section  of  the  Cologne  Academy  for  Practical 
Medicine,  old  tuberculin  is  employed  for  all  forms  of  surgical 
tuberculosis,  operative  treatment  being  limited  as  much  as 
possible.  Bungart  [279]  observed  in  many  cases  a  striking 
increase  in  strength  and  appetite  and  sometimes  also  a  favourable 
effect  on  the  temperature.  Present  experience  shows  that  the 
domain  of  specific  treatment  is  in  those  forms  of  the  disease  in 
which  conservative  measures  are  considered  sufficient,  but  also 
necessary  operations  are  no  contra-indication  for  tuberculin 
treatment. 

Here  also  Jochmann  has  had  wide  experi- 
vjocnmann.  ence  and  expresses  his  opinion  as  follows  : 

"  In  tuberculosis  of  the  bones  and  joints  we  had  in  many  cases 
a  quite  striking  improvement  in  the  general  condition.  The  effect 
on  the  local  trouble  was  varied.  One  case  of  tuberculosis  of  the 
foot  healed,  others  of  tuberculosis  of  the  glands  and  joints  with 
fistulas,  in  spite  of  prolonged  treatment,  showed  no  change.  I 
consider  that  surgical  treatment  takes  the  first  place  for  the  im- 
provement of  local  symptoms  in  the  treatment  of  tuberculosis  of 
the  bones  and  joints,  but  that  tuberculin  treatment  is  of  the 
greatest  importance  as  an  aid,  especially  as  tubercular  bone 
trouble  is  not  generally  the  only  localization  of  the  tubercular 
virus,  but  usually  tubercular  glands,  bronchial  or  mesenteric, 
are  also  present,  which  are  dangerous  to  the  patient  and  therefore 
require  to  be  cured." 

Meyer  [264]  similarly  recommends  the 
combined  surgical-specific  treatment  "  in  all 
cases  of  open  bone  and  joint  tuberculosis  with  fistulas;  whether 
an  operation  scar  has  incompletely  closed  with  fistula  formation 
or  tubercular  abscesses  have  broken  out — complete  healing  can 
almost  always  be  obtained  by  simultaneous  surgical  and  tuber- 
culin treatment." 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  267 

We  ourselves  have  published  reports  on  the 
Bandelier  and        action  of  TR  in  tubercular  joint  and  bone 

Roepke.  affections    [280].      Of    the    two    classes    of 

Use  of  TR.  case>    tne    one    treated    conservatively    with 

general  remedies,  the  other  with  abscess  and  fistula  formation 
which  had  to  be  submitted  to  resection,  both  also  treated  with 
tuberculin,  we  gained  the  impression  that  the  cavities  remaining 
after  the  resection  of  the  diseased  ends  of  the  joints  rid  them- 
selves more  easily  of  the  tissue  to  be  thrown  off  than  we  had 
formerly  been  in  the  habit  of  seeing. 

.  Brunzlow  also  reports  a  case  of  tuberculosis 

Brunzlow.  of  thg  knee_j0jnt  which,  in  spite  of  opening 

Knee-joint.  an<j  cieansjng  0f  the  joint  and  the  use  of 

iodoform-glycerine  injections  and  Bier's  congestion,  visibly  grew 
worse.  After  four  treatments  with  TR,  repeated  at  intervals  of 
several  months,  a  complete  cure  was  obtained  with  good  action 
of  the  joint. 

Recently  Powker  and  D'Arcy  Power  have 

reported  on  the  favourable  action  of  TR  in 

D'Arcy  Power  and  surgical     tuberculosis;     Sonnenburg,     too, 

W.   Neumann.        saw    g0Od    results    in    tuberculosis    of    the 

joints.     W.  Neumann  [277]  obtained  a  perfect  cure,  even  when 

accompanied  by  extensive  pulmonary  tuberculosis,   in  fungus  of 

the  joint  and  cold  abscesses  in  caries  of  the  bone.     He  considers 

TR,  bacillarv  emulsion,  and  tuberculinum  purum  to  be  equal  in 

their  action. 

,  ,  The  latest  modification  of  specific  treatment 

Rosenbacn  s         .g  Rosenbach>s  method ;  he  has  used  it  in  a 
Method.  larg-e    and    varied     selection     of     cases    of 

surgical  tuberculosis  (joints,  vertebra,  tendon-sheaths,  glands, 
fistular  abscesses  of  subcutaneous  tissue),  generally  with  the  help 
of  various  surgical  methods,  and  has  had  considerable  and 
lasting  success.  Wherever  possible  he  injects  the  tuberculin 
direct  into  the  focus ;  he  considers  the  subcutaneous  method  only 
advisable  in  cases  where  direct  application  is  impossible.  The 
value  of  the  treatment  is  confirmed  by  H.  Curschmann,  who  cured 
a  case  of  tubercular  periostitis,  also  by  Seyberth,  who  witnessed 
considerable  improvement  in  eight  out  of  ten  cases  of  local 
tuberculosis. 

Marmorek's  anti-tubercular  serum  has  been 
Marmorek's  Serum.   increasingIy     used     in     cases     of    surgicai 

tuberculosis.  Favourable  verdict  is  given  bv  Bassano,  Dubard, 
Lewin,  v.  Rotschild,  Brunier,  Hvmans  and  Polak  Daniels, 
Uhry,    Sikemeier,    Miihsam,    Strauss,    Schenker,    and   Weitling. 


268  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

Wein  was  able  to  report  a  favourable  effect  in  each  of  his  fifty- 
nine  cases.  Sonnenburg  noted  a  striking  cure  of  tubercular 
disease  of  the  rectum,  which  he  had  treated  in  vain  surgically. 
And  other  favourable  results  were  observed  in  the  Moabite 
Hospital,  reported  on  by  van  Huellen.  Recently,  however,  he 
has  become  somewhat  more  reserved  in  his  estimate  of  the  serum ; 
now  prefers  the  subcutaneous  injection,  and  application  per 
rectum,  which  often  produces  trouble  in  the  intestine,  he  regards 
onlv  as  a  makeshift. 

The  judgment  of  Hoffa  [281]  is  the  most  favourable  of  ali, 
on  the  basis  of  results  in  forty  cases  of  osteal  and  arthritic  disease. 
He  obtained  improvement  in  cases  which  had  defied  every  other 
form  of  treatment  for  years.  In  twenty-two  cases  under  long 
observation  he  saw  18  per  cent,  of  cures  and  the  same  striking 
improvement,  never  any*  harm  or  unpleasant  secondary  action 
after  he  has  begun  to  employ  the  Marmorek  serum  per  rectum. 
He  recommends  it,  however,  always  in  combination  with  other 
well-proved  remedies  and  methods. 

_.  ,      _  After  Glaessner  [282!  had  seen  these  results 

Glaessner  s   Success  .     TT   r,  ,  L.      J  ,  . 

in  Hoffa  s  cases,  he  experimented  on  a  large 

scale  in  the  Surgical  University  Polyclinic- 
Marmorek's  Serum.  g0  ^at  no  mistake  might  be  made,  only  out- 
patients were  treated  under  quite  unchanged  domestic  and  hygienic 
conditions,  internal  medicaments  as  far  as  possible  avoided,  and 
the  local  disease  processes,  fistulas  and  ulcers  treated  with  quite 
inert  remedies.  Only  in  cases  of  tuberculosis  of  the  joints  were 
the  most  necessary  surgical  measures  resorted  to  :  puncture  of 
abscesses,  rest,  and  clearing  of  the  joints,  with  Bier's  congestion. 
Of  100  patients,  seventy-two  were  treated  for  a  long  time  per 
rectum,  without  any  undesirable  secondary  symptoms  arising, 
except  temporary  diarrhoea  in  a  few  cases  when  the  injections  had 
been  administered  several  days  in  succession.  From  the  detailed 
accounts  of  forty-eight  cases,  the  following  results  are  evident  : 
Many  cases  of  spina  ventosa-  show  no  specific  effect  from  the 
serum  ;  the  same  is  true  of  the  cases  of  tuberculosis  of  the  bones 
and  joints  in  which  there  was  a  closed  process,  whereas  in  open 
forms,  especially  in  fistulas  of  the  bone  of  long  standing  there  was 
at  least  for  a  time  a  diminution,  and  often  a  rapid  absorption  of 
the  secretion  ;  one  case  of  tuberculosis  of  the  sheaths  of  tendons 
remained  unaffected ;  the  most  striking  was  the  diminution  and  in 
some  cases  the  total  disappearance  of  swollen  lymphatic  glands. 
Glaessner  considers  the  chief  advantage  to  be  the  extraordinarily 
favourable  influence  on  the  general  condition  which  almost  always 
takes  place,  and  which  would  in  itself  alone  justify  the  use  of  the 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  269 

serum.     Altogether  he  considers  Marmorek  serum  in  conjunction 

with  other  proved  methods  of  treatment  as  a  valuable  weapon  in 

the  campaign  against  surgical  tuberculosis. 

.  .  On  the  other  hand,  Hohmeier's  reports  are 

Unfavourable  ,     ,  ,  ,  ■  , 

very  reserved ;  he  could  not  see  signs  or  a 

ports.  definite  curative  influence  of  the  serum  even 

in  slight,  fresh  disease  of  the  bones  and  joints ;  in  cases  of  average 

severity,    and    in    severe    cases    it    was    completely    ineffectual. 

Preleitner  also   saw   no   results   in    tuberculosis   of   the   joints   in 

children.     Sonntag  also  says  that  the  curative  action  of  the  serum 

is  difficult  to  estimate. 

,  Lenzmann   [278]   draws  the  following  con- 

Lenzmann  s  ,      .  f        'i        ■>  ■     ,        ,■<■ 

elusions   irom    the   above   surgical   publica- 

Conclusions  as  to  tjonS-  j±  precise  surgical  indication  for  the 
Use  of  Serum.  application  of  the  serum  must  not  be 
neglected.  It  should  be  employed  when  conservative  treatment 
is  permissible  on  other  grounds,  and  when  it  is  a  question  of 
hastening  the  result  of  an  operation  and  of  ensuring  its  success. 
In  all  such  cases  the  critical  estimation  of  a  real  cure  is  rendered 
very  difficult,  as  it  often  involves  prolonged  periods  of  treatment, 
in  the  course  of  which  many  a  surprising  change  for  the  better 
may  occur.  Still  the  favourable  reports  are  so  numerous  that 
specific  antitoxic  powers  cannot  be  denied  to  the  serum.  Harmful 
results  have  not  been  noticed  in  surgical  tuberculosis.  The 
method  of  application  per  rectum  is  uncertain.  Further  study  of 
the  effectiveness  of  the  remedv  is  desirable. 


10.—  TUBERCULOSIS  IN  CHILDHOOD. 

All  that  has  been  said  of  tuberculin  treatment  for  the  adult 
applies  also  to  children,  but  even  greater  care  is  indicated. 

After  Ganghofner  in   1905  and  a  year  later 
IS  °r^'  Jessler,     declared    themselves    disciples    of 

tuberculin  treatment,  and  tested  it  in  cases  of  infantile  tubercu- 
losis, the  question  was  more  closely  considered,  but  tuberculosis 
of  the  glands  and  surgical  tuberculosis  remained  the  principal 
subject  of  therapeutic  inquiry.  In  1907  Engel  [283]  in  an  excel- 
lent treatise  on  the  reasons  for  believing  in  the  curabilitv  of 
pulmonary  tuberculosis  in  children,  only  thought  it  advisable  that 
experiments  should  be  made  with  tuberculin,  on  the  result  of 
which  was  to  depend  whether  "a  definite  specific  treatment  of 
tuberculosis  in  children  should  be  inaugurated  or  whether  all  such 
experiments  were  to  cease."  In  the  meantime  tuberculin  had 
already   found   its   way   into   some   children's    hospitals   and   the 


270  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

experiences  collected  from  such  hospitals  (for  example  those  of 
von  Landgraff  and  W.  Goetsch)  were  favourable.  Also,  accord- 
ing to  the  information  given  by  K.  Pannwitz  the  results  at  the 
Hohenlychen  Red  Cross  Children's  Hospitals  were  considerably 
improved  by  the  assistance  of  tuberculin  treatment ;  the  children 
increased  on  an  average  more  in  weight  and  lost  the  tubercle 
bacilli  in  46*5  per  cent,  of  cases,  as  against  25  per  cent,  when  the 
hygienic-dietetic  treatment  was  used  alone.  But  especially  the 
recent  work  of  Schlossmann  and  his  assistants,  Bauer  and  Engel, 
has  opened  up  more  hopeful  prospects  as  regards  pulmonary 
tuberculosis  in  children. 

..  Although    according    to    recent    investiga- 

tions, especiallv  those  of  Hohlfeld,  there  is 
Treatment  of        in  thg  lungs  of"  suckIings  who  have  died  of 

Sucklings.  tuberculosis  an  occasional  tendency  to  heal, 

yet  the  prognosis  of  tuberculosis  in  sucklings  is  a  very  unfavour- 
able one  (Weigert,  Schlossmann,  Xaegeli,  Stirnimann  and  Geipel, 
Hamburger  and  Sluka,  Engel,  and  others).  The  fact  is  therefore 
important  that  Schlossmann  [284]  has  succeeded  by  systematic 
treatment  with  tuberculin  in  bringing  sucklings  safely  and  in  good 
condition  through  the  most  dangerous  year,  the  first  year  of  life ; 
whereas  other  sucklings,  not  treated  specifically,  but  cared  for  in 
other  respects  like  the  former,  died. 

_  Hitherto,    in    treating   tuberculosis   in   chil- 

dren,  very  much  smaller  doses   have  been 
for  Children.         uged  than  with  adultS(  and  a  beginning  has 

been  made  in  small  children  with  one-tenth,  with  bigger  ones  with 
\  to  \  of  the  dose  prescribed  for  adults.  The  maximal  dose, 
too,  has  remained  correspondingly  lower  than  that  for  adults. 
Schlossmann  also  begins  with  small  doses  ('01  to  o'i  c.mm.  of 
old  tuberculin)  and  especially  at  the  beginning  of  the  cure  uses 
the  mild  form  of  treatment  in  a  cautious  manner,  carefully  adapted 
to  the  individual,  but  without  entire  avoidance  of  slight  or 
moderate  reactions ;  he  seeks,  however,  to  reach  exceptionally  high 
doses,  greatly  exceeding  those  given  hitherto  (2,000,  sometimes 
even  5,000  c.mm.  of  old  tuberculin).  But  he  points  out  emphati- 
cally that  this  method  applies  only  to  children  in  the  first  year  of 
life.  He  thus  maintains  the  principle  we  have  upheld  for  years, 
that  tuberculin  treatment  should  begin  with  small  loses  leading 
up  to  large  doses,  a  principle  which,  however,  so  often  appears 
to  be  misunderstood  and  has  no  connection  with  and  is  bv  no 
means  identical  with  the  production  of  severe  reactions.  Schloss- 
mann finds  support  for  the  expediency  and  necessity  of  large  doses 
of   tuberculin    in    the    interesting   investigations   of   his   assistants 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  2JI 

Engel  and  Bauer  (c/.  above),  who  with  the  help  of  fixation  of  com- 
plement were  able  to  prove  that  the  tubercular  children  treated 
with  tuberculin  showed  in  their  serum  a  formation  of  antibodies 
in  proportion  to  the  size  of  the  tuberculin  dose.  But  the  proof 
of  the  presence  of  such  antibodies  was  only  obtained  in  the 
children  when  inoculated  with  ioo  c.mm.  of  old  tuberculin  and 
upwards.  So  the  aim  of  tuberculin  treatment  must  be  to  enable 
the  child's  body,  by  doses  systematically  increased,  according  to 
the  individual  susceptibility,  to  tolerate  the  quantities  necessary 
for  an  active  formation  of  antibodies.  And  the  formation  of 
antibodies  must  be  maintained  by  the  prolonged  injection  of  the 
larger  doses — about  500  to  2,000  c.mm.  every  five  to  eight  days. 
Schlossmann  describes  tuberculin  as  the  best  therapeutic  aid  in 
the  campaign  against  tuberculosis  in  children. 

_        .         .   _,  ,      In  a   verv  detailed  work   Tiool    Engel  and 

Engel  and   Bauer  s    n  '      ,     ,  +u  .L      ,J  ,    .  °       ,. 

0  Bauer  published  the  results  of  their  studies 

Conclusions.  of  the  pathology  and  treatment  of  children's 
tuberculosis,  which  contain  the  clinical  and  experimental  proofs  of 
the  above  conclusions  of  Schlossmann.  The  special  result  of 
these  investigations  can  be  summarized  in  the  following  state- 
ments, which  we  emphasize  on  account  of  the  fresh  guidance  they 
afford  for  tuberculin  treatment. 

All  tubercular  children  who  are  free  from  pulmonary  tuber- 
culosis are,  without  exception,  suited  for  tuberculin  treatment,  so 
that  there  are  scarcely  any  contra-indications. 

The  latent  form  of  tuberculosis,  only  manifested  by  the  posi- 
tive tuberculin  reaction  and  scrofula,  must — from  the  point  of 
view  of  formation  of  antibodies — be  considered  as  specially 
favourable  for  specific  treatment. 

Fresh  cases  of  pulmonary  tuberculosis,  above  all  progressive 
cases,  are  not  suitable  for  treatment  with  tuberculin. 

Lung  processes  of  small  extent  with  but  little  tendency  to 
increase  are  amenable  to  cautious  treatment  with  tuberculin. 

The  younger  the  children,  the  smaller  appears  the  prospect 
of  cure. 

A  low  state  of  nutrition  is  to  be  considered  rather  as  an  indi- 
cation than  as  an  contra-indication. 

Fever  is  not  an  absolute  contra-indication  ;  in  many  cases 
fever  can  be  got  rid  of  by  small  doses  of  tuberculin. 

The  investigations  of  Engel  and  Bauer  would  seem  to  have 
proved  that  the  child's  organism — independent  of  age — is  not  so 
susceptible  to  tuberculin  in  cases  of  localized  tuberculosis  as  was 
hitherto  supposed;  that  the  degree  of  susceptibility  to  tuberculin 
is  not  only  dependent  upon  the  extent  of  the  tubercular  process, 


2J2  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

but  also  on  its  activity  and  tendency  to  increase,  i.e.,  on  the 
prognosis. 

So  cases  of  localized  tuberculosis  of  glands, 
Indications  and       boneg  and  ^^  with  favourable  prognosis 

Contra-indications.  are  ^tt\e  susceptible  to  tuberculin  and  easily 
rendered  immune  to  it.  Pulmonary  tuberculosis  tending  to 
increase  and  of  unfavourable  prognosis  is  extremely  susceptible 
to  tuberculin  and  scarcely  open  to  systematic  treatment.  They  are 
borne  out  in  this  conception  by  Heubner,  Soltmann,  Escherich 
and  others,  who  also  failed  to  attain  satisfactory  results  with  the 
smallest  doses  of  tuberculin,  and  preferred  to  abstain  from  using 
tuberculin  altogether  in  cases  of  pulmonary  tuberculosis  in 
children.  Slighter  cases  of  pulmonary  tuberculosis  tending  to 
become  stationary,  and  mostly  situated  in  the  upper  portions  of 
the  lung,  form  intermediate  cases. 

Jochmann  obtained  good  results  in  cases  of  pulmonary  tuber- 
culosis in  children  over  3  years  of  age.  But  here  also  it  was 
only  a  question  of  slight  cases  of  apical  disease,  with  but  little 
dulness  and  thickening  in  the  Rontgen  picture.  Tuberculin 
treatment  of  pulmonary  tuberculosis  in  sucklings  was  unsuc- 
cessful. 

No  Fundamental     From  the  works  of  Schlossmann,  Engel'and 

r^.m  .  Bauer,    we  see   not   only  that  the  different 

Difference  between  .,  ...  .11-         r    iU        u -i  1 

susceptibility    to    tuberculin    of    the    child 

Tuberculin  Treat-    organism     [s    explained    by    one    uniform 
ment  of  fundamental    law,    but   to    our   surprise   we 

Adults  and  Children.  aiso  iearn  from  these  extensive  publications 
that  the  mode  of  reaction  to  tuberculin  is  in  the  main  the  same  in 
cases  of  tuberculosis  in  adults  and  in  children.  And  so  we  can  no 
longer  acknowledge  any  fundamental  difference  in  the  therapeutic 
use  of  tuberculin  in  adults  and  in  children  in  contradistinction  to 
Engel  and  Bauer,  who  still  maintain  a  difference  owing  to  lack  of 
personal  experience  in  tuberculin  treatment.  Moreover,  their 
method  of  treating  pulmonary  tuberculosis  is  almost  absolutely 
identical  with  our  proposals  for  the  treatment  of  adults  with  old 
tuberculin,  both  as  regards  the  initial  doses,  graduation  of  dose, 
the  best  maximum  dose,  the  interval,  the  length  of  treatment,  and 
the  general  principle  underlying  the  treatment. 

We  may  pick  out  two  important  points  from  these  careful  and 
very  thorough  investigations  which  show  the  progress  made  :  — 

(1)  An  important  contribution  to  the  fixed  laws  of  the  action 
of  tuberculin  on  the  tubercular  organism. 

(2)  Fresh  support  given  to  the  utility  of  modern  tuberculin 
treatment  as  we  advocate  it,  from  the  clinical  and  biological  point 
of  view. 


THE     SPECIFIC     TREATMENT     OF     TUBERCULOSIS  273 

.  .        ...   ,  ....  The  method  of  large  doses  of  tuberculin  for 

Unsuitability  ,  .,  .  r         ,  , 

children  has  not  found  very  general  recog- 

of  the  Method  of  nition>  Toeplitz  recommends  it  with  slight 
Large  Doses.  modifications  for  ambulant  treatment. 
Baginsky,  Citron,  Cohn,  Escherich,  Ganghofner,  Hamburger  and 
Monti,  Jochmann,  Weddy-Poenicke,  and  Wolff-Eisner  have 
expressed  themselves  adversely.  J.  Neumann  reports  the  obser- 
vation of  complete  change  of  temperature  and  subnormal  depres- 
sions. Fuchs  in  thirteen  cases  of  surgical  tuberculosis  and  five 
cases  of  tuberculosis  of  the  apices  did  not  observe  a  single  success, 
but  often  even  a  bad  result.  Rohmer  [285],  too,  could  not  prove 
this  treatment  to  be  frequently  successful,  although  clinically  a 
striking  curative  effect  was  found  with  regard  to  scrofulous  sym- 
ptoms and  anatomically  an  abnormally  strong  proliferation  of 
connective  tissue,  especially  in  the  region  of  pulmonary  foci,  to 
which  phenomena  Dautwiz  has  repeatedly  drawn  attention. 
When  continuous  use  of  large  doses  was  made,  in  most  cases 
hypersusceptibility  set  in,  and  it  seemed  as  if  large  doses  of  tuber- 
culin had  a  prejudicial  effect  on  the  general  well-being  of  the 
children.  Also,  in  spite  of  prolonged  treatment,  the  extension  of 
the  tubercular  process  did  not  always  cease.  Rohmer,  therefore, 
advises  a  return  to  the  moderate  doses  formerly  used. 

Treatment  ^e   treatment   of   tuberculosis   in    children 

u,,  c~,^n   r»~  ~  commencing  with  very  small  doses  gradu- 
by  bmall   Doses,       .,  °  ,  .     -    .  .  & 

_       .      ,.     ,  ,  ally   increased   receives   increasing   recogni- 

Gradually  Increased  ,•  "       T,    „  .  ,  ^    ,      .  . 

7  tion.      thus     experts     such     as     Escherich 

Preferable.  ancj    v>    Pirquet    consider    the    method    ex- 

tremely valuable  as  long  as  there  is  no  manifest  tuberculosis  but 
only  lymphatism,  pallor,  and  weakness,  with  positive  cutaneous 
reaction  ;  for  such  cases,  ambulant  tuberculin  treatment  is  also 
thoroughly  suitable.  Cronquist  and  Wittich  have  also  just 
published  very  favourable  results  in  a  suitable  selection  of  cases. 
The  latter,  issuing  his  report  from  the  Royal  University  Clinic  in 
Berlin,  gives  an  equally  warm  recommendation  of  the  ambulant 
tuberculin  treatment  of  children  suffering  from  scrofula,  incipient 
tuberculosis  and  tuberculosis  of  the  bronchial  glands.  The 
results  can  be  summarized  thus  :  Cough,  pain  in  the  chest  and 
stitch  disappear;  night-sweats  cease;  diarrhoea  gives  place  to  a 
normal  stool ;  the  appetite,  weight,  and  general  condition  improve; 
scrofulous  signs,  phlyctens,  and  tuberculides  of  the  skin  vanish. 
When  should        When   should  the  tuberculin   injections   be 

t   ,  ..     T       ,      commenced  in  childhood? 

Tuberculin  Treat-  tut  o^ 

L   _  v.    Leube    [286]     expresses    our    own 

ment  Commence?  opinion   in  the  fol]owing  quotation  .     «  As 

18 


274  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

we  may  assume  that  tuberculin   treatment  increases  the  specific 

resistance     of     the     organism     to     the     toxins     of     the     tubercle 

bacillus     and     counteracts     their     harmful     effects,      the     cure 

should  be  begun  as  early  as  possible  in  order  that  the  transition 

from  the  closed  form  of  tuberculosis  to  the  open  form  may  be 

prevented.     The   best    method    of   procedure    is,    in    the    case   of 

children    of    tubercular    parents,    to    make 

a  ue  °  repeated  v.  Pirquet  tests  so  as  to  determine 

Cutaneous  Test.      the  time  of  the  first  infecti0n  with  tubercle 

bacilli.  Such  diagnostic  tuberculin  tests  repeated  at  fixed  inter- 
vals by  the  family  physician  or  dispensary  doctor  belong  to  the 
regular  medical  family  supervision,  the  necessity  of  which  is  justly 
receiving  increased  recognition.  As  soon  as  a  positive  v.  Pirquet 
reaction  is  observed,  tuberculin  treatment  should  be  commenced. 
The  cure  must  last  several  months,  and  should  be  repeated  later; 
it  can  be  carried  out  by  the  physician  at  home  or  in  a  dispensary, 
in  the  health  resort  or  sanatorium." 

Lastly,  v.  Leube's  injunction  is  in  agreement  with  the  old 
demand  of  Koch — to  discover  all  early  forms  of  tuberculosis  by 
the  aid  of  tuberculin  diagnosis  and  to  cure  them  with  tuberculin 
before  they  reach  the  stage  of  open  tuberculosis.  Since  1897 
Petruschky  has  been  especially  enthusiastic  in  his  unremitting 
recommendation  of  this  method  of  combating  the  disease.  After 
the  discovery  of  v.  Pirquet's  test,  A.  Krause  [287]  again  brought 
it  into  recognition  by  advising  the  systematic  performance  of  the 
cutaneous  test  on  all  children  from  2  years  of  age  upwards,  and ' 
curing  those  that  react  by  tuberculin  treatment  before  they  reach 
the  school-going  age.  In  the  last  place,  Citron  [288]  at  the 
International  Tuberculosis  Congress  at  Rome  in  191 2  has 
developed  the  same  idea  and  demands  a  systematic  fight  against 
the  disease  in  childhood.  On  the  ground  of  all  our  biological 
knowledge  and  our  clinical  and  experimental  experiences  in  tuber- 
culin therapy  we  may  assume  that  the  resistance  of  the  organism 
infected  by  the  tubercle  bacillus  is  so  raised  by  tuberculin,  especi- 
ally bacillary  emulsion,  that  manifest  tuberculosis  does  not 
develop.  He  emphasizes  the  fact  that  this  method  must  be 
adopted  on  the  larger  scale  "  if  a  serious  attempt  is  to  be  made  to 
solve  the  great  and  difficult  problem  of  the  fight  against  manifest 
tuberculosis." 


Conclusion. 


..  ,  r  ^        .c       There  lies  before  us  a  record  of  numberless 

Value  of  Specific  ,  ,  ,,  ,,        ,-rr        <_    j        + 

r  successful    results    in    the    different    depart- 

Treatment  ments  of  tubercular  disease,  results  obtained 

Esfablished.  with  all  kinds  of  products  and  substances 

from  the  tubercle  bacillus  by  active  immunization  and  with  serum. 
Passive  immunization  seems  to  prove  useful  only  in  a  certain 
percentage  of  cases  of  initial  and  purely  local  (especially  surgical) 
tuberculosis.  In  spite  of  the  success  thus  obtained,  the  future  of 
the  specific  treatment  lies  in  the  direction  of  active  immunization, 
tuberculosis  possessing  all  the  characteristics  of  a  chronic  disease. 
The  results  hitherto  attained  confirm  this  view.  Perhaps  further 
progress  may  lead  to  a  combination  of  active  and  passive  immuni- 
zation. At  any  rate,  in  face  of  the  great  mass  of  accumulated 
facts,  belief  in  the  value  of  specific  treatment  cannot  be  any  longer 
withheld.  Future  research  may  perhaps  succeed  in  finding  a 
better  remedy,  a  universal  panacea  for  the  disease ;  we  hope  and 
desire  it.  But  the  present  generation  cannot  spare  the  time  to 
wait  for  this ;  practitioners  and  patients  alike  are  thrown  back 
on  the  remedies  now  available.  And  of  these  remedies  the  value 
of  the  tuberculins  is  too  little  known  and  appreciated,  first  and 
foremost  among  them  being  the  preparations  of  Koch  as  the  most 
tried  and  approved.*  To  help  to  assure  them  the  position  they 
deserve  in  extending  the  healing  art  and  adding  to  the  comfort 
of  the  suffering  whom  we  all  serve,  has  been  the  sole  object  of 
this  book. 

~  r        A  few  words  of  defence,  as  were  necessarv 

Opponents  of       .  '  3 

'  in   former   editions,    are   no   longer   needed 

Tuberculin.  +      ,  ^u       .  ,  .  , 

to-day.      1  he  time  when   a  certain   number 

*  It  should  be  noted  here  that  in  Germany  tuberculin  is  subjected  to  a 
Government  test,  without  which  it  may  not  be  sold.  This  test  is  an  absolute 
necessity  in  view  of  the  large  number  of  preparations  which  home  and 
foreign  industry  has  put  on  the  market.  It  is  the  only  guarantee  for 
uniformity  of  preparation  and  will,  it  is  hoped,  lead  to  reduction  of  pre- 
parations in  use  to  some  of  the  best  proven.  We  emphasize  the  importance 
of  this  Government  test,  as  there  is  no  reference  to  it  on  the  tuberculin  bottles 
nor  on  the  accompanying  circulars. 


276  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

of  our  colleagues  lost  no  opportunity  of  emphasizing  their  dissent 
with  more  or  less  skill,  dignity  and  urbanity,  is  over.  There 
is  no  longer  an  open  feud  against  tuberculin.  Tuberculin  is 
recognized  as  the  one  highly  specific  remedy  in  tuberculosis,  and 
the  general  feeling  is  expressed  by  the  words  of  F.  Klemperer 
[289]  :  "  I  have  no  right  to  say  that  tuberculin  is  not  an  effective 
remedy  " ;  or  some  go  so  far  as  to  say  with  him  that  they 
consider  "  tuberculin  a  good  auxiliary  in  the  treatment  of  tuber- 
culosis." Each  is  entitled  to  his  own  opinion,  and  we  only  claim 
the  right  to  oppose  error,  timid  doubt,  and  blind  faith  where 
their  fruits  counteract  progress  urgently  demanded  by  the  state 
of  affairs.  But  we  cannot  pass  over  the  voices  and  ignorant 
statements  of  recent  anti-tuberculin  literature  without  a  word  of 
disapproval.  Whilst  more  or  less  reservedly  recognizing  the 
value  of  tuberculin,  they  object  to  the  extent  of  its  employment; 
this  extended  use  seems  to  us  not  only  possible,  but,  in  the 
interests  of  a  successful  fight  against  tuberculosis,  absolutely 
necessary.  Tuberculin  is  no  longer  openly  and  definitely  rejected 
as  this  would  be  too  committal,  but  doubts  and  objections  are 
raised  which,  although  without  any  real  justification,  are  able  to 
do  harm.  For  the  practitioner  is  more  attentive  to  the  cry  of 
warning  than  to  the  warmest  expression  of  approval,  and  prefers 
to  wait  rather  than  to  act,  as  he  supposes,  prematurely.  It  is 
to  these  tactics,  which  are  intended  to  retard  the  victorious  work 
of  specific  diagnosis  and  therapy,  that  we  object. 

In  the  interests  of  truth  and  accuracy,   we 
lagnosis.  will  first  turn  to  the  question  of  tuberculin- 

diagnosis.  Schroeder  [290],  in  his  recent  work,  "  Tuberculin 
Treatment,"  summarizes  the  section  on  tuberculin  diagnosis  as 
follows:  "The  chief  result  of  the  debate"  (at  the  yearly  Con- 
gress of  Sanatorium  Doctors,  at  Diisseldorf,  in  191 1)  "was  the 
rejection  of  tuberculin  as  a  diagnostic  agent  for  the  recognition 
of  active  tuberculosis  in  adults."  What  was  really  said  at  this 
Congress?  Meissen  [291],  who,  in  his  lecture,  "Experiences 
with  Tuberculin,"  expressly  denies  that  he  has  been  converted 
from  a  Saul  to  a  St.  Paul  in  the  question  of  tuberculin,  says  that 
he  considers  the  value  of  tuberculin  lies  more  in  its  use  as  a 
diagnostic  agent  than  as  a  therapeutic  remedy.  Ulrici  [112] 
opened  the  discussion  on  the  "  Question  of  Tuberculin  for 
Ambulant  Practice  "  and  in  speaking  of  the  diagnostic  use  of 
tuberculin  gave  his  opinion  that  no  help  in  practical  diagnosis 
of  adults  is  to  be  gained  from  the  local  tuberculin  tests  and  that 
the  subcutaneous  test  should  be  excluded  from  ambulant  practice. 
In   the   discussion   which   followed  Junker   disagreed   and   stated 


CONCLUSION  277 

that  tuberculin  diagnosis,  used  with  observance  of  the  various 
early  symptoms  of  the  disease,  is  a  valuable  adjuvant,  but  should 
only  be  employed  by  doctors  possessing  considerable  experience. 
Koch  observed  focal  reactions  after  test  injections  a  good  deal 
oftener  than  Ulrici,  and  they  never  caused  any  harm  ;  he  had  also 
never  been  able  to  convince  himself  of  the  danger  of  the  conjunc- 
tival test  performed  on  the  healthy  eye.  Krause,  on  the  contrary, 
had  but  seldom  recognized  definite  focal  reactions,  and  has  often 
seen  conditions  which  can  be  described  as  harmful,  and  which 
lasted  for  some  time.  Curschmann  considers  the  diagnostic  tuber- 
culin test  used  for  the  diagnosis  of  pulmonary  patients  for  sana- 
torium treatment  worthless.  Brecke  took  precisely  the  opposite 
view;  he  held  that  Koch's  test  together  with  other  methods  of 
examination  will  always  remain  a  most  valuable  adjuvant  in 
diagnosis,  and  is  absolutely  indispensable  if  as  many  tubercular 
subjects  are  to  be  diagnosed  in  the  initial  stage  as  possible,  as  is 
demanded  by  the  very  principle  of  the  campaign  against  tubercu- 
losis and  the  scheme  of  National  Insurance.  Ulrici  then  explained 
that  he  only  rejected  the  local  tuberculin  tests,  and  the  subcu- 
taneous in  ambulant  practice.  But  even  if  his  opinion  be  counted 
as  unconditionally  opposed  to  the  value  of  tuberculin  diagnosis. 
Schroeder's  statement  is  an  absolute  misrepresentation  of  the  facts, 
quite  different  and  opposed  to  what  was  really  said ;  there  were  at 
the  Diisseldorf  Congress  at  least  as  many  voices  raised  for  tuber- 
culin as  a  diagnostic  agent  as  against  it.  Therefore  it  is  deplorable 
that  Schroeder,  who  has  certainly  had  no  very  wide  experience  in 
this  branch,  sets  his  own  judgment  over  other  and  more  competent 
authorities,  misrepresenting  them,  even  partly  reversing  their  real 
views  and  in  one  sentence  misleading  the  less  read  medical  world. 
Although  personal  polemics  are  very  distasteful  to  us,  we  desire  to 
see  this  matter  righted,  in  order  that  Schroeder's  criticism  of  tuber- 
culin diagnosis  shall  at  any  rate  not  find  its  way  from  medical  to 
public  literature  without  refutation.  As  a  rule  the  very  fact  that 
it  was  a  bequest  from  Robert  Koch  will  itself  protect  the  specific 
diagnosis  of  tuberculosis  from  rejection.  Let  us  realize  the  ten 
years'  fruitless  effort  to  find  a  specific  reaction  for  syphilis,  which 
has  given  us  the  Wassermann  test,  but  which  is  even  now  not 
always  and  for  all  cases  absolutely  certain.  Or  we  can  compare 
the  still  unsatisfied  desire  for  a  specific  reaction  for  carcinoma. 
Then  we  shall  fully  realize  the  fundamental  significance  of  the 
epoch-making  and  practical  tuberculin  diagnosis.  It  will  not  be 
disposed  of  by  a  single  sentence  or  a  single  discussion,  not 
even  limited  by  a  few  records  of  so-called  tuberculin  damage. 
What  do  we  learn  from  Penzoldt  and  F.  Kraus,  two  university 


278  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

professors  certainly  not  prejudiced  in  favour  of  specific  diagnosis  ? 
Penzoldt  [105]  states  that  the  disadvantages  of  the  subcutaneous 
test  are  negligible;  and  Kraus  [258]  but  a  short  time  ago  in  a 
post-graduate  lecture  for  practitioners  made  the  following  state- 
ment with  reference  to  pulmonary  tuberculosis  :  "  Every  injection 
of  tuberculin  brings  about  quite  a  characteristic  condition  in  the 
tubercular.  According  to  the  severity  of  the  reaction,  muscular 
pains,  languor,  increased  pulse-rate,  nausea,  fever  and  headache 
occur.  With  these,  after  twenty-four  to  thirty-six  hours,  the 
signs  of  a  local  reaction  appear — increased  sputum,  catarrhal 
sounds,  stitch  on  the  diseased  side,  sputum  containing  bacilli  and 
changes  in  the  physical  signs.  As  all  these  symptoms  soon  dis- 
appear and  give  place  to  an  increased  feeling  of  well-being,  we 
have  no  ground  for  any  special  fear  of  them.  How  favourable  an 
effect  an  injection  may  have  can  be  easily  seen  in  ulceration  of 
the  larynx  which  is  visible  to  the  eye,  in  which  distinct  anatomical 
changes  are  seen  after  each  injection,  first  in  the  direction  of 
aggravation  of  the  condition,  then  of  a  healing  process.  Simi- 
larly it  is  possible  to  demonstrate  the  anatomical  effect  on  tuber- 
lar  changes  in  the  lung." 

Treatment  ■  ^e    now    come    t0    tne    therapeutic    use  of 

^  .       tuberculin.    It  is  true  that  harm  has  resulted 

on  the  Ground       ,  ;.  ,  _,  ,  ,.      ,        iU . 

from  the  use  of  tuberculin,  but  this  was  in 

ot  Resulting  a  previous  ep0ch,  the  early  stage  of  develop- 

Harm  ;  ment,    a   time   in   which    the   first   attempts 

were  made  on  unsuitable  material  and  based  also  on  a  false  view 
of  the  action  of  the  remedy,  heedless  of  the  warnings  and  cautions 
of  Robert  Koch.  The  few  more  recent  unfavourable  reports  are  all 
to  be  referred  to  faulty  application  or  unsuitable  selection  of  cases. 

Moreover,  it  is  a  fact  that  the  unfavourable  or  less  satisfactory 
results  are  recorded  by  observers  who  have  had  but  little  experi- 
ence of  the  method,  and  that  they  receive  no  confirmation  from 
clinicians  who  have  for  years  worked  with  the  remedy.  It  may 
be  asserted  that  not  a  single  case  has  been  published  in  which 
the  alleged  harm  has  resulted  from  the  mild,  reactionless  method 
of  administration  recommended  by  us.  All  this  should  make  one 
wonder  whether  the  harm  has  not  been  a  consequence  of  a  faulty 
method,  and  whether  it  could  not  have  been  avoided  with  certainty 
by  carefully  following  the  directions,  indications  and  contra-indi- 
cations.  And  the  conviction  is  brought  yet  nearer  home  when 
we  see  men  of  scientific  attainment  formerly  opponents  of  tuber- 
culin become  advocates  of  it  after  working  for  years  with  the 
modern  mild  method  of  administration  and  assuring  themselves 
not  merely  of  its  safety  but  of  its  superiority  to  other  treatment. 


CONCLUSION  279 

And  the  number  of  these  specialists  and  clinicians  has  lately 
enormously  increased  with  the  increased  use  of  tuberculin  prepara- 
tions— a  numerical  and  living  proof  that  there  is  no  danger  of 
harm  from  the  use  of  tuberculin  with  the  modern  system  of  injec- 
tion. 

In  the  second  place,   its  opponents  adduce 
on  the  Ground       ^   fact   that   tuberculin   generally   fails  to 
of  Animal  cure  tjie  artinciai   infection  of  guinea-pigs 

Experiment.  an^  rabbits.     Here  it  must  be  admitted  that 

the  cure  of  infected  animals  by  means  of  tuberculin  preparations 
has  only  been  attended  with  success  in  the  hands  of  the  few 
workers  who  have  specially  taken  up  this  laborious  investigation  : 
for  example,  R.  Koch,  Kitasato,  Bujwid,  C.  Spengler,  Pfuhl, 
Donitz,  Klebs,  Yamagiva,  Sattler,  Centanni,  Landmann, 
Christian,  and  Rosenblat.  Other  observers  (such  as  Baumgarten, 
Alexander,  Gasparini,  Mercanti,  Baas,  Popoff,  Liebmann, 
Metchnikoff,  Roux,  Buchner,  Laffert,  and  recently  Stumpff 
and  Haupt  [292])  observed  neither  inhibition  nor  healing  of 
tuberculosis  in  experimental  animals.  The  positive  observations 
are,  however,  not  to  be  denied,  and  are  not  rendered  less  credible 
by  the  experiments  of  Krusius  [293],  who,  in  artificial  intra- 
corneal  tuberculosis  of  rabbits,  recognizes  a  relative  protection 
afforded  by  prophylactic  tuberculin  injections,  but  no  real  healing 
action  of  therapeutic  injections.  It  is  true,  too,  that  Titze  did  not 
succeed  in  curing  tubercular  guinea-pigs  by  tuberculin,  but 
showed  that  the  tissue-reactions  caused  by  the  tuberculin  treat- 
ment are  the  commencement  of  the  healing  processes  which  result 
in  encapsulation  of  the  tubercle  bacilli  in  the  tissues.     The  usual 

.  .        ...  ....        .      small    animals    such    as    guinea-pigs    and 

Unsuitability  of  .  ,  .  .    .  m.  ui 

rabbits  are  certainly  very  unsuitable  expen- 

Animals  Used.       mental  subjects.       The  artificially  infected 

guinea-pig  invariably  dies  of  general  tuberculosis  after  injection 

of  the  smallest  quantity  of  living  tubercular  material  even  in  a 

dilution  of  1  : 1,000,000,000. 

_x.         _,  .       There  are,   too,   a  large  number  of  further 

Other  Reasons  for  V  .1  .-  -*u 

reasons    why    a    therapeutic    attempt    with 

INon-success.  tuberculin  in  animals  does  not  run  parallel 
with  the  tuberculin  treatment  of  man.  Kraemer  [294]  has  stated 
amongst  others  the  following  :  The  conditions  of.  healing  are 
altogether  unlike  in  man  and  animals;  the  absolutely  different 
behaviour  of  the  organism  to  certain  infections  and  toxins  is  a 
matter  of  common  knowledge ;  there  is  a  fundamental  difference 
in  the  manner  of  the  natural  and  of  artificial  infection  in  animal 
experiment;  artificial  infection  in  the  small  body  of  the  experi- 
mental animal  is  always  much  too  severe. 


280  TUBERCULIN    IN     DIAGNOSIS    AND    TREATMENT 

Further,    immunizing    experiments    in    ani- 
Necessity  tor        malg  ghow  that  jmmunjty  t0  tuberculosis  is 

Long  Treatment.  legs  compiete  and  less  stable  than  immunity 
to  other  infectious  diseases.  This  will  hold,  too,  for  man.  There- 
fore we  advise  a  prolonged  course  of  tuberculin  treatment  (by  the 
family  doctor,  &c),  so  as  to  maintain  tox-immunity  and  produc- 
tion of  antibodies  and  to  avoid  relapse.  As  Schroeder  states  that 
he  has  specially  often  observed  relapses  in  highly  immunized 
tubercular  individuals,  we  must  state  precisely  the  opposite — that 
amongst  many  hundreds  of  highly  immunized  patients  kept  for  a 
long  time  under  observation,  we  have  not  made  such  observations. 
It  must  lastly  be  borne  in  mind  that 
iews  °  v.    Behring,    in    his    studies    of    tubercular 

v.   Behring  and       immunity,     gave    up     experimenting    with 
Neufeld.  rabbits  and  guinea-pigs  on  account  of   its 

great  difficulty.  "  The  task  of  rendering  a  guinea-pig  tuberculo- 
immune,"  v.  Behring  says,  "  is  actually  more  difficult  than  that 
of  immunizing  cattle,  and  this  is  principally  due  to  the  fact  that 
the  sequence  and  dosage  of  the  agents  cannot  be  determined 
without  accurate  registration  of  temperature  and  body-weight,  of 
the  local  and  general  tissue  changes,  of  the  alterations  of  the 
blood,  &c."  Hence  we  have  a  right  to  demand  at  any  rate  experi- 
ment on  larger  animals,  of  which  cattle  are  specially  suitable. 
Neufeld  also  [295],  long  a  co-worker  of  Koch's,  is  of  the  opinion 
that  the  bovine  infection  of  cattle,  well  known  to  be  of  milder 
course  and  with  tendency  towards  spontaneous  cure,  has  a  far 
closer  analogy  to  human  tuberculosis.  And  in  fact  v.  Behring 
has  recorded  the  excellent  healing  action  of  old  tuberculin  on 
tubercular  cattle.  McFadyean  and  Pearson  and  Gilliland,  too, 
have  succeeded  in  producing  a  high  degree  of  immunity  with 
tuberculin  in  cattle  suffering  from  bovine  infection  and  artificially 
infected. 

N  r         The  second  edition  of  our  handbook,    "  A 

y  Clinical  System  of  Tuberculosis  "  (Bale  and 

Combination  with    Danielsson>   IQI2)  makes  it  quite  clear  that 

General  Treatment.  we  agree  with  the  general  hvgienic-dietetic 
treatment  of  tubercular  patients.  We  consider  the  combination  of 
the  two  modern  factors — sanatorium  and  tuberculin  treatment — 
the  most  efficacious  method  of  treatment  for  active  pulmonary 
tuberculosis  at  present  available,  especiallv  when  the  disease  has 
passed  the  initial  stage.  We  are  emphasizing  here  the  combina- 
tion with  non-specific  treatment  because  the  value  of  sanatorium 
treatment  seems  to  lie  in  two  directions  :  (1)  It  affords  the  exclu- 
sion of  all  harmful  factors  of  the  workers'  dailv  life,  of  the  home, 


CONCLUSION  28l 

of  the  persistent  exposure  to  infection,  and  of  an  unhygienic  mode 
of  life  in  the  fullest  sense,  factors  which  have  so  extraordinarily 
powerful  an  influence  in  so  many  chronic  diseases.  (2)  The 
general  treatment — physical,  dietetic  and  hydriatic— is  intended 
to  strengthen  the  resistance  of  the  organism,  to  increase  its  total 
vital  energy,  and  to  stimulate  the  depressed  and  weak  by  rest  or 
methodical  exercise.  We  advocate  this  standpoint  without  the 
value  of  general  hygienic-dietetic  treatment  of  tubercular  patients 
having  been  proved  by  experiments  on  animals.  But  we  ask  the 
opponents  of  tuberculin,  who  to-day  only  call  themselves  sceptics, 
what  would  be  left  of  the  whole  armoury  of  our  treatment  of  phthisis 
if  the  same  demand  were  made  of  the  generally  recognized  cura- 
tive factors,  especially  of  the  hygienic-dietetic  regime — that  they 
should  cure  experimental  animals.  No  such  proof  is  needed  by 
the  physician  who  has  worked  for  any  length  of  time  "  lege 
artis  "  with  tuberculin.  More  convincing  than  experiments  on 
animals  is  one's  own  personal  accurate  observation  and  experience 
at  the  bedside,  to  which  Sahli  rightly  alone  admits  authority  in 
the  tuberculin  question,  as  in  all  questions  of  therapy. 

/-v  r     When,  after  a  standstill  in  the  rate  of  mor- 

Co-operation  of        ,.       '  ,  , 

tality  from  tuberculosis,  the  numbers  again 
Medica 

decreased    and    sank    to    the    lowest    point 

Fraternity.  hitherto  reached,   it  seemed  as  if  our  great 

organization  against  tuberculosis  had  reached  the  limits  of  its 
powers ;  but  it  has  now  been  strengthened  and  advanced  by  the 
more  extensive  use  of  specific  therapy.  Once  more  we  must 
strive  to  the  goal  which  we  have  had  in  view  for  years  :  the  co- 
operation of  all  medical  men,  especially  general  practitioners,  in 
the  treatment  of  tuberculosis  and  with  specific  remedies.  Experi- 
ences have  been  so  completely  sifted  and  the  results  so  thoroughly 
tested  that  tuberculin  by  the  new  method  can  be  recommended  to 
a  much  larger  circle  of  physicians  for  their  own  use. 

,-,  r  We  now  possess  a  definite  well-based  tuber- 

r*i  (-*  £1  ^  O  Ft  ^     TOP 

'      ,  culin  therapy,  that  of  the  mild,  gentle  form 

Large  Number  of      r      ,     •    •  ,     ..  rr,.i,.  .     ,, , 

°  01  administration.      1  his  tact  is  not  altered 

Tuberculins.  ^y     t^e    comparativelv     large     number     of 

preparations   recommended  and   the   varietv    in    the    methods  of 

administration  proposed,  which  is  complained  of  by  F.  Klemperer 

[289]  and  others,  and  which  has  been  interpreted  as  a  sign  of  the 

failure  of  tuberculin  treatment.     This  is  not  so.       Tuberculin  is 

no   universal   cure  for  tuberculosis;   the   limits   of   its  power  are 

sufficiently  known.       What  is  more  natural   than  by  continued 

reasearch  and  freshly  acquired  knowledge  to  seek  more  effective 

immunizing  substances?     The  fate  of  other  remedies  such  as  iron 


282  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

and  iodine  is  exactly  similar ;  what  a  vast  number  of  preparations, 

but  who  would  doubt  the  value  of  the  substance  common  to  them 

all?     This  is  scientific  progress;  a  standstill  means  retrogression. 

Just  as  in  treatment  with  iron,  salicylates,   mercury  and  iodine, 

so  in  tuberculin  treatment  the  result  depends  less  on  the  choice  of 

the  preparation  than  on  its  correct  employment.     Moreover,  there 

_  are    really    only    two    essentially    different 

y      ,  kinds  of  tuberculin — old  tuberculin  prepara- 

Different  Kinds  of  dons  and  bacillary  preparations;    all  others 

Tuberculin.  are  unimportant  modifications.    The  mildest 

representative  of  the  first  group  is  albumose-free  tuberculin  (AF), 

with  which  the  practitioner  can  work  most  successfully.     If  it  is 

necessary  to  employ  a  bacillary  preparation,   we  can  recommend 

as  the   mildest   of  all   the   sensitized  bacillary   emulsion   (SBE) ; 

further  details  have  been  given  in  the  separate  chapters  on  the 

tuberculins. 

We  consider  it,  therefore,  the  problem  of 
Tuberculin  the  the  present  day  to  introduce  tuberculin 
Concern  of  the  treatment  into  general  medical  practice. 
General  Practitioner.  ^ne  recognition  of  its  efficacy  makes  this 
not  only  our  right,  but  duty.  It  is  true 
that  those  practitioners  who  have  only  just  given  up  the  fight 
against  tuberculin,  and  also  some  who  know  and  value  the 
curative  power  of  tuberculin,  are  not  yet  quite  of  this  opinion. 
But  the  majority  of  German  medical  men  greet  the  efforts  to  lift 
them  out  of  their  passivity  with  regard  to  the  treatment  of  this 
national  disease  and  to  equip  them  for  successful  personal  treat- 
ment of  their  tubercular  patients  with  great  interest  and  under- 
standing of  the  importance  and  difficulty  of  the  task.  The  further 
development  of  the  tuberculin  question  will  not  take  place  without 
work  and  without  struggle.  We  fear  neither  and  will  continue  to 
strive  for  the  introduction  of  tuberculin  treatment  into  general 
practice,  an  event  both  necessary  and  possible.  But  one,  perhaps 
rather  personal,  remark  we  should  like  to  make  :  the  man  who 
considers  or  has  considered  tubercle  bacilli  as  harmless  sapro- 
phytes will  find  it  very  difficult  to  understand  the  use  of  tubercu- 
lin ;  and  these  less  old-fashioned  physicians  who,  till  a  short  time 
ago,  rejected  tuberculin  in  every  form,  should  be  the  very  last  to 
set  local  limits  to  tuberculin  treatment,  which  they  now  recognize 
as  useful,  limits  which  should  cripple  us  in  the  campaign  against 
tuberculosis  as  a  national  disease. 

A     ,     ,  As  regards  ambulant  tuberculin  treatment, 

Ambulant  &       ...        .  ,    . 

we  must  distinguish  between  two  different 
Treatment;  ,  •     ,        ,  N  ,.        ,.  ,  ,    . 

kinds  :    (1)   a   continuation   and   completion 


CONCLUSION  283 

of  a  course  of  tuberculin  treatment  begun  in  an  institution,  but 
interrupted  prematurely,  or  (2)  a  course  begun  and  carried  on 
outside  the  institution  by  a  practitioner  according  to  his  own 
judgment. 

In   the   first   case   we   are   considering   sub- 
After  Sanatorium     sequent    treatment   as   an    out.patient   after 

Treatment.  sanatorium   treatment.     For  the  considera- 

tion of  this  question  it  is  necessary  to  study  the  kind  of  patient 
and    length    of   treatment    in    the    public    sanatoria    and    private 
institutions. 
Public  Sanatorium    Patients  who  go  to  sanatoria  consist  (accord- 
ing   to   the   Turban-Gerhardt   division    into 
Treatment  too       stadia)  Qn  ^  average  of  one-third  so-called 
Short  for  Complete  initjal  caseSj  about  two-thirds  being  patients 
Cure.  [n  the  second  and  third  stadia  of  pulmonary 

tuberculosis;  yet  the  average  period  of  treatment  in  the  public 
sanatoria  is  only  ten  to  thirteen  weeks.  This  period  is  not  long 
enough  to  cure  or  to  bring  to  a  standstill,  with  cessation  of 
sputum  or  of  the  bacilli  in  the  sputum,  tuberculosis  spread  over 
two  or  more  lobes  of  the  lung,  generally  not  even  when  the 
sanatorium  treatment  is  combined  with  the  use  of  tuberculin. 
The  latter  must  be  used  in  carefully  graduated  doses  and,  if 
possible,  without  producing  reaction,  so  that  on  an  average  only 
twenty  to  twenty-four  tuberculin  injections  are  possible  in  the 
sanatorium.  This  generally  succeeds  in  removing  all  general 
toxic  symptoms  and  incites  the  production  of  antibodies,  which 
assist  the  curative  processes  at  the  site  of  disease.  But  hardly 
ever  with  so  short  a  course  of  treatment  is  that  high  degree  of 
tox-immunity  reached  which  is  accompanied  by  a  continuous 
ample  supply  of  antibodies,  promoting  the  diminution  and  clear- 
ing of  the  tubercular  process,  the  disappearance  of  rales,  sputum 
and  bacilli  and  offering  some  guarantee  against  relapse.  To 
accomplish  this,  much  larger  doses  of  tuberculin,  continued  for 
a  much  longer  time,  are  necessary.  The  result  of  the  shortness 
of  the  combined  sanatorium  and  tuberculin  treatment  is  that  in 
the  more  advanced  cases  the  source  of  infection  is  not  dried  up, 
the  good  general  condition  arrived  at  disappears  again  more  or 
less  quickly,  the  tubercular  focus  with  its  toxic  influences  gets 
the  upper  hand  and  leads  gradually  to  the  patient  becoming 
worse,  a  process  which  it  is  often  impossible  to  arrest,  even  by 
a  second  course  of  treatment  in  the  sanatorium. 

So  the  doctors  of  the  institutions  are  really,  as  Weicker 
expressed  it,  "  working  on  a  torso."  "  The  patient  generallv 
comes  to  us  with  well-pronounced  disease;  the  length  of  the  stay 


284  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

depends  upon  his  economic  conditions ;  he  often  leaves  us  at  a 
time  when  a  clinical  cure  is  impossible.  What  happens?  We 
discharge  him  with  good  advice,  advice  which  in  the  struggle 
for  existence  he  is  generally  not  in  a  position  to  follow.  A 
temporary  improvement,  a  postponement  of  death  has  been 
achieved,  but  not  a  cure ;  therefore  the  practitioner  must  be  asked 
to  continue  at  home  what  the  institution  has  begun."  And  this 
means  nothing  less  than  preventing  patients  capable  of  being 
cured  from  passing,  after  discharge  from  the  sanatorium,  into  a 
condition  which  cannot  be  cured. 

Now  the  proposal  might  be  made  that  such  cases  should  be 
kept  longer,  until  clinically  healed,  in  the  institution.  This 
would  certainly  be  the  surest  way.  What  can  be  done  by  com- 
bined cures  of  a  sufficient  duration  we  have  recently  shown  [149]  : 
In  the  treatment  of  500  patients  in  open  tuberculosis  of  Turban's 
Stadium  I,  it  was  successful  in  100  per  cent,  of  the  cases,  in 
Stadium  II  in  87  per  cent.,  and  in  Stadium  III  in  44  per  cent. 
in  attaining  lasting  disappearance  of  sputum  or  of  tubercle  bacilli 
in  the  sputum.  But  the  question  of  expense  is  generally  an 
obstacle  both  for  private  and  public  sanatorium  patients. 

The  very  liberal  grant  received  to-day  in  the  insurance 
scheme  [in  Germany]  will  probably  be  continued  on  the  same 
scale,  although  the  expenditure  for  the  treatment  of  tuberculosis 
has  during  the  last  few  years  amounted  to  double  the  sum 
estimated.  At  any  rate,  we  cannot  reckon  upon  the  length  of  the 
treatment  in  sanatoria  being  extended  in  the  future,  and  clinical 
cure  in  cases  past  the  initial  stage  will  remain  infrequent.  Treat- 
ment will  therefore  in  many  cases  only  be  able  to  lay  the  founda- 
tion on  which  the  practitioner  will  have  to  build,  in  order  to  cure 
the  cases  of  tuberculosis  which  leave  the  sanatoria  not  cured  but 
capable  of  being  cured.  And  for  this  purpose  no  remedy  is 
anything  like  so  efficacious  as  tuberculin. 

Private  Sana  ^e  concutions  m  private  sanatoria  are  just 

the  same.     The  course  of  treatment  is  cer- 
torium  ,    •    1         r.         ,  1  .1  .1 

tainly    often     longer,     but    the    cases,     the 

Treatment.  selection  of  which  is  not  subjected  to  any 

legal  restrictions,  are  much  worse.  So  it  is  a  matter  of  daily 
observation  that  paying  patients,  in  spite  of  longer  treatment, 
do  not,  as  a  rule,  remain  long  enough.  In  the  large  majority 
of  cases  this  is  due  to  expense.  Those  who  are  aware  of  the 
conditions  know  that  the  cost  of  a  cure  lasting  many  months  is 
not  covered  by  the  income  of  men  of  the  middle  classes  or  of 
officers  and  the  higher  public  officials,  and  a  premature  cessation 
of  the  cure  is  necessary  unless  they  have  private  means.     It  is 


CONCLUSION  285 

also  very  doubtful  policy  to  spend  the  last. penny  of  one's  savings 
on  treatment  in  the  sanatorium,  because  after  discharge  the 
conditions  of  life  and  nourishment  should  be  as  good  as  possible, 
and  so  extra  expenditure  is  necessary.  At  any  rate,  in  all  cases 
when  the  treatment  is  prematurely  interrupted,  that  is  before 
clinical  cure  has  been  accomplished — and  this,  according  to  our 
experience,  is  the  general^  rule — the  private  doctor  will  have  to 
continue  the  treatment  with  injections  of  tuberculin  if  really  per- 
manent results  are  to  be  arrived  at,  the  doctor  of  the  institution 
having  been  forced  to  leave  the  cure  unfinished  owing  to  the 
pressure  of  external  circumstances. 

, .    r         . ,  The  practical  possibility  of  ambulant  tuber- 
Unfounded  ,.   r  r  J  .  ,      ,.„ 

_,  .       .  culm     treatment     is     estimated     differently, 
Obiections  to  ,.  ,,  .  ..      .  -     / 

J  according    to    the    point    01    view    of    the 

Ambulant  Treat-     individual    critic.      Sceptics    see    difficulties 
rnept-  everywhere,   often  where  none  exists;  they 

generalize  upon  or  exaggerate  certain  inconveniences  until  they 
become  unsurmountable  obstacles,  and  this  in  the  twentieth 
century,  when  social  conditions  are  of  the  greatest  interest  and 
when  millions  are  being  spent  in  the  campaign  against  tuber- 
culosis !  Many  an  over-anxious  adherent  of  tuberculin  would 
like  to  prevent  it  from  again  being  brought  into  discredit  by 
uncontrolled  and  reckless  use  in  general  practice.  Such  anxiety 
shows  the  highest  recognition  of  the  value  of  tuberculin.  But 
in  this  respect  we  certainly  do  not  need  to  be  more  cautious  than 
Koch  himself,  who,  after  his  first  experience,  .  would  certainly 
not  have  risked  the  reputation  of  his  preparations  of  tuberculin 
in  handing  them  over  to  general  practitioners.  Koch  evidently 
was  no  longer  afraid  of  this  when  he  wrote  in  the  introduction 
to  the  third  edition  of  this  text-book  :  "I  also  agree  in  recom- 
mending specific  treatment  for  out-patients,  naturally  with  the 
most  careful  selection  of  cases."  In  these  words  Koch  approves 
of  our  standpoint,  that  with  the  modern  use  of  tuberculin  certain 
precautions  are  sufficient  to  guarantee  on  the  one  hand  the  success 
of  ambulant  treatment,  on  the  other  hand  to  exclude  the  possibility 
of  evil  results. 

Sanatorium  ^e  precautionary  measures  demanded  for 

,-,   ..  ,,       clinical    treatment    hold    °"ood    too    in    the 

Patients  specially        ,  _  & 

subsequent  treatment  of  out-patients.        In 

Oil  itofi      fY")  p  . 

this  case  only  such  patients  are  treated  as 

Subsequent  Tuber-  nave  aireacjy  been  treated  specifically  in  the 

culin  Treatment,     institution,     have    overcome    the    first    and 

greatest  difficulties,  and  after  the  course  of  tuberculin  treatment 

have  been  considered  suitable  by  the  doctors  of  the  institution  for 


286  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

continued  treatment  as  out-patients.  Thus  any  mistake  in  the 
choice  of  patient  is  excluded.  A  selection  can  also  be  made  so 
that  only  serious,  steady,  conscientious  patients  are  suggested  for 
subsequent  ambulant  treatment  and  the  nature  of  their  calling  and 
the  distance  from  the  doctor  taken  into  consideration. 

Such  patients  also  have  the  necessary  experience  in  the 
regular  taking  of  the  temperature,  the  proper  behaviour  after 
injection,  the  observation  of  their  own  symptoms,  ascertaining 
the  body-weight,  &c,  and  so  make  individual  treatment  and  judg- 
ment easier  for  the  doctor.  Finally  the  doctors  of  the  institution, 
who  by  long  observation  are  intimately  acquainted  with  the 
details  of  the  case,  can  give  the  general  practitioner  certain 
directions  for  the  continuance  of  the  treatment. 

If  it  is  added  that  this  specific  after-treatment  of  out-patients 
should  be  purely  optional,  that  it  should  not  be  forced  upon 
either  the  patient  or  his  private  or  club  doctor,  then  everything 
has  been  said  to  ensure  its  success. 

The       option       of       ambulant       tuberculin 

Ambulant  treatment    without    the    previous    combined 

Treatment  without   sanatorium     and     tuberculin     treatment     is 

Previous  Sana-       important.      We   do    not   want   to   be   mis- 

torium  Treatment,    understood.     We  do  not  in  any  way  want 

to  underestimate  the  work  and  importance 
of  the  hospital  and  sanatorium ;  they  are  absolutely  necessary  and 
will  remain  so ;  and  the  present  plan  of  providing  sanatoria  for 
the  middle  classes  can  only  be  greeted  wTith  great  satisfaction. 
But  the  radius  of  their  work  is  not  sufficient  in  the  campaign 
against  tuberculosis  as  a  national  disease,  even  when,  after  intro- 
duction of  National  Insurance  and  the  insurance  of  private 
employes,  more  than  one-third  of  the  population  are  included. 
What  is  to  happen  to  the  non-insured  when  they  fall  victims  to 
tuberculosis  ?  And  even  if  it  were  possible  financially  and 
economically  to  place  all  cases  of  tuberculosis  without  delay  in 
the  sanatoriums  for  treatment,  there  would  not  be  room  for  them. 
All  the  164  sanatoria,  with  their  15,863  beds  for  adults  and 
children  and  an  average  of  three  months'  treatment,  can  take 
in  all  something  like  63,500  phthisical  patients  yearly,  leaving 
about  half  a  million  patients  to  the  general  practitioners  for  ambu- 
lant treatment.  In  view  of  these  figures  a  certain  feeling  of  help- 
lessness is  natural.  Little  is  achieved  by  good  medical  advice  as 
to  rest,  nutrition  or  water-treatment,  for,  as  a  rule,  the  patient  in 
the  course  of  his  everyday  life  is  unable  to  carry  out  this  advice 
in  such  a  way  as  to  effect  a  cure.  Very  slight  is  the  therapeutic 
effect  of  preparations  of  creosote  and  guaiacum  or  of  the  modern 


CONCLUSION  287 

and  latest  preparations,  .the  curative  value  of  which  is  usually 
doubtful  or  stands  in  no  proportion  to  the  price.  The  only 
remedy  specific  in  its  action  is  tuberculin,  so  that  practitioners 
will  have  to  decide  to  use  it  as  long  as  no  more  effectual  remedy 
is  available  for  ambulant  treatment.  In  such  a  situation,  no 
debate  can  alter  matters  nor  any  conclusions  such  as  that  arrived 
at  in  the  Diisseldorf  Congress  of  Sanatorium  Doctors  (September, 
191 1),  according  to  which  a  profitable  tuberculin  cure  in  private 
practice  may  be  recognized  as  possible,  but  that  there  is  no  reason 
to  desire  or  promote  its  wider  employment.  The  admission  of 
possibility  has  been  more  than  justified  by  I  he  facts,  and  the 
second  part  of  the  sentence  over-estimates  the  powers  of  the 
sanatoria  in  the  fight  against  tuberculosis  and  completely  fails  to 
realize  what  is  really  necessary — the  active  therapeutic  coalition 
of  all  practitioners.  As  sanatorium  physicians  we  feel  compelled 
to  hope  that  for  phthisical  patients  who  are  suitable  for  specific 
treatment  but  who  for  any  reason  are  excluded  from  sanatorium 
treatment,  a  successful  ambulant  tuberculin  cure  may  be  allotted. 
Therefore  we  also  hold  it  our  duty  so  to  help  our  colleagues  in 
private  practice  that  they  may  learn  to  employ  the  specific  treat- 
ment of  tuberculosis  according  to  the  individuality  of  the  par- 
ticular case  and  with  the  greatest  possible  certainty.  Thus  we 
hope  by  therapy  and  prophylaxis  to  extend  the  fight  against 
tuberculosis  to  the  widest  circles  of  our  nation,  and  not  only  to 
combat  the  chronic  ill-health  and  danger  of  infection  of  thousands, 
but  also  to  counteract  a  thriving  swindle  in  various  bogus 
methods  of  treatment  and  quack  remedies. 
Objections  on  the    Then  lt  ls  objected  that  the  use  of  tuberculin 

*->  -1     r  on   out-patients  and  the  necessity  involved 

Ground  of  ,        ,  ; r  ,  J    .    ,.     „ 

.         01     taking     the     temperature     periodically 
Interference  with  1    „  .*  c  ,        ...       . 

makes  the  exercise  of  a  man  s  calling  lmpos- 

or  ■  sible.     This  may  sometimes  be  the  case  but 

quite  exceptionally,  as  according  to  the  industrial  regulations 
there  is  in  all  industries  a  maximum-  day's  work,  broken  by 
periods  of  rest.  But  there  is  nothing  to  prevent  the  doctor  from 
certifying  the  patient  as  unfit  for  work  at  the  commencement  of 
the  tuberculin  treatment,  which  then  entitles  him  to  the  receipt  of 
sick-pay,  wages,  &c.  In  the  case  of  patients  who  are  still  or 
again  fit  for  work,  Saturday  is  the  best  time  for  the  injection  of 
the  large  doses  which  are  less  frequently  needed,  as  they  get 
Sunday  for  rest.  Everything  depends  on  the  agreement  and 
willingness  of  the  patient  and  the  doctor  to  use  tuberculin  treat- 
ment. That  the  independent  middle  class,  those  whose  work  is 
mental,    housewives   and   members   of  the   family  who    have    no 


288  TUBERCULIN    IN    DIAGNOSIS     AND    TREATMENT 

calling  cannot  spare  time  for  the  treatment,  cannot  be  seriously 

maintained.     For  staying  in  bed  or  special  care  is  not  necessary 

during  tuberculin   treatment   for  the  initial  forms  of  pulmonary 

tuberculosis   which   are   the   most   important   cases   for  ambulant 

treatment. 

_.  .  iI        It  is  further  objected  that  the  recommenda- 

Objection  on  the      .  .  ,     ,  ;  ,  ,.        ,       ,         , 

J  tion     of     ambulant     tuberculin     treatment 

oun      °  entails  further  consideration  and  that  indi- 

Ivlisuse.  vidual  practitioners  are  not  capable  of  con- 

ducting it.  It  is  said  that  unsuitable  tubercular  cases  and 
non-tubercular  patients  would  be  "  injected,"  and  suitable  cases 
unsuitably  treated  with  tuberculin  ;  febrile  patients  would  under- 
take drives  and  railway  journeys  of  some  hours  to  reach  their 
doctor  for  the  injections ;  others  would  be  treated  without  exact 
control  of  the  temperature  being  observed,  or  some  would  not 
take  the  temperature  at  all  during  the  treatment ;  doctors  would 
even  supply  their  patients  with  tuberculin  dilutions  and  syringes 
for  their  own  use.  We  will  not  dispute  the  occurrence  of  these 
"  outgrowths,"  but  should  prefer  to  designate  them  by  the  term 
"  quackery  "  and  condemn  them  most  severely.  But  we  believe 
these  to  be  exceptional  cases  which,  with  a  suitable  and  correctly 
performed  ambulant  cure,  will  decrease  and  disappear.  In  what 
province  of  medicine  and  applied  science  in  general  are  there  no 
such  outgrowths,  no  mistakes,  no  errors  in  technique  ?  Ought, 
therefore,  all  practitioners  to  be  withheld  or  even  forbidden 
tuberculin  treatment  on  principle,  merely  because  a  few  deny  its 
value  or  misuse  it  ? 

General  Prac-       ^e     opponents     of     ambulant     treatment 

....  ~        ,  ,       r  undoubtedly  over-estimate  the  difficulties  of 

titioners  Capable  of  ._ .     ■     J  .  .     . 

_        ,       .   '     .  specific  therapy  of  tuberculosis ;  in  any  case 

Conducting  Am-      .,  .  .    ,,    .   .,  J  .  , 

&  they  are  not  so  great  that  they  cannot  be 

bulant  Treatment.  overcome  by  all  doctors,  who  daily  have 
more  difficult  tasks  put  before  them.  Careful  observation  of  the 
temperature,  correct  valuation  of  the  subjective  troubles,  con- 
tinuous control  of  the  objective  condition,  of  the  pulse  and  the 
weight  are  the  most  important  factors  in  tuberculin  treatment,  and 
at  the  same  time  their  guiding  lines.  Do  not  let  us  forget  that 
to-day  we  are  only  dealing  with  the  mild  method  of  administra- 
tion, if  possible  without  reaction,  to  gain  success  in  which,  in 
addition  to  the  points  just  mentioned,  time  is  the  most  important 
factor.  The  man  who  can  take  his  time  in  increasing  the  dose 
and  in  the  sequence  of  the  injections,  will  never  do  any  harm  : 
and  the  general  practitioner  has  this  time,  as  the  patient  can 
quietly  proceed  with  the  duties  of  his  calling. 


CONCLUSION  289 

As  far  as  the  selection  of  cases  of  tubercu- 
Selection  of         losis  fof  ambulant  tuberculin   treatment  is 

Cases.  concerned,  we  have  expressed  our  opinion 

in  detail  in  earlier  chapters.  We  have  a  sufficiently  high  opinion 
of  the  conscientiousness  of  general  practitioners  to  believe  that 
before  beginning  the  treatment  they  will  make  sure  that  active 
tuberculosis  is  present  and  in  doubtful  cases  when  necessary  get 
the  opinion  of  an  experienced  specialist,  who  can  then  decide 
whether  ambulant  tuberculin  treatment  shall  be  tried  or  whether 
it  would  be  better  to  postpone  or  dispense  with  it  altogether. 
According  to  our  experience  these  are  not  difficulties  but  matters 
of  course.  Further,  it  is  really  evident  that  tuberculin  will  not 
be  tried  for  psychotherapeutic  reasons  by  the  practitioner  as  an 
ultimum  remedium,  but  that  he  and  also  the  novice  will  limit  their 
specific  treatment  to  the  initial  stages  of  pulmonary  tuberculosis 
and  its  favourable  cases  and  more  chronic  forms.  A  case  of 
phthisis  accompanied  by  more  or  less  continual  fever  is,  even  in 
the  initial  stage,  no  object  for  ambulant  tuberculin  treatment.     It 

Unsuitable  Condi-   is   true   that   we  as   sanatormm   physicians 
,    _      .  value    Koch's    bacillary    emulsion    as    the 

tions   and    Environ-  ..  ,.r  ,    .■;  ,     ,      ,   , 

most  excellent  antifebrile  remedy  tor  tuber- 

ment  tor  Am-  cuiar  fever,  but  attempts  to  reduce  fever 
bulant  Treatment.  wjth  tuberculin  are  not  suitable  for  ambu- 
lant practice.  In  addition,  harm  will  generally  be  done  by 
tuberculin  in  the  case  of  badly  nourished  tubercular  patients. 
One  tries,  on  the  contrary,  to  fortify  the  organism  by  hyper- 
nutrition,  to  raise  its  resistance  and  power  of  assimilation. 
If,  on  economical  grounds,  hyper-nutrition  is  impossible  or 
when  attempted  is  unsuccessful,  it  is  better  to  dispense  with 
tuberculin;  we  do  the  same  in  the  sanatorium.  Where, 
also,  there  is  no  time  for  regular  measurement  of  tempera- 
ture, where  a  fresh  air  cure  by  night  and  rest  for  a  few 
hours  daily  is  impossible  owing  to  restricted  conditions  of  housing 
in  the  heart  of  a  manufacturing  quarter  or  to  pressure  of  house- 
hold duties,  where  hydrotherapeutic  measures  such  as  wet  packs, 
friction,  or  baths  are  impracticable,  where,  lastly,  there  is  no 
sense  of  personal  hygiene  and  prophylaxis — then  tuberculin  injec- 
tions alone  will  not  prevent  the  advance  of  tubercular  disease ; 
therefore  it  is  best  to  spare  oneself  and  others  the  disappointment 
which  must  follow.  We  do  not  fear,  however,  that  in  such  cases, 
where  the  pulmonary  process  is  not  too  far  advanced  or  too 
progressive,  direct  harm  will  be  done  by  ambulant  tuberculin 
treatment.       But  no  good  will  be  done,  because  the  permanent 

19 


290  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

disadvantages  and  harmful  effects  of  the  surroundings  outweigh 
all  and  leave  no  possible  surplus  of  curative  factors. 

Thus  for  ambulant  tuberculin  treatment,  just  as  for  many 
surgical  and  gynaecological  measures,  there  is  a  social  indication 
and  contra-indication  which  merit  careful  attention,  as  they  exert 
a  great  influence  on  the  final  result  of  ambulant  treatment. 

And  what  about  the  capacity  of  the  practitioner  to  conduct 
tuberculin    cures?       One    must    oneself    have    been    a    "mere" 
general    practitioner    fully    to    appreciate    the    offensiveness    of 
criticism  which,   without  reason,   casts  doubt  upon  the  capacity 
and  feeling  of  responsibility  of  the  majority  of  the  medical  pro- 
fession  just   because  a   few   merely   make   haphazard    injections 
instead  of  conducting  a  methodical  course  of  tuberculin  treatment. 
We  regret  the  expression  of  such  feeling  on  the  part  of  high 
authorities,   as  it  cannot  conduce  to  the  reputation  of  the  pro- 
Necessity  for  Wide-  fession-     Deeds,  too,  are  more  useful  than 
any     amount     of     self-satisfied     criticism! 
spread   Instruction    ,<  f,  ,      .  .  ,  t  ,  «. 

r  .  hvery     physician     can     learn     tuberculin 

in  Tuberculin       treatment,  and  he  must  learn  it."    Based  on 
Treatment.  this  motto  0f  Penzoldt's,    let   us  enlist  all 

sanatorium  doctors  to  aid  us  as  appointed  guides  for  the  thera- 
peutic fight  against  tuberculosis.  Let  us  continue  to  draw 
general  practitioners  into  our  sphere  of  work.  Let  us  instruct  all 
who  require  and  demand  information  and  a  thorough  understand- 
ing of  specific  treatment.  In  such  a  widespread  disease  there  is 
work  enough  for  us  all.  Let  us  try  on  our  own  initiative  or 
with  the  help  of  the  German  Central  Committee  for  the  campaign 
against  tuberculosis,  or  by  post-graduate  classes,  to  arrange 
courses  of  lectures,  in  which  by  demonstration  of  the  technique 
of  tuberculin  treatment,  by  introduction  of  patients  and  by  tuber- 
culin charts  it  may  be  made  evident  to  the  general  practitioner 
how  simple  the  modern  mild  method  really  is.  Two  years'  pre- 
paration, as  has  been  demanded,  is  certainly  not  necessary  to 
master  the  specific  treatment.  Such  an  extensive  demand  is  quite 
impracticable  and  would  make  the  treatment  solely  the  affair  of 
specialists;  this  is  just  what  we  want  to  avoid,  for  we  should 
strive  to  combat  tuberculosis  universally,  wherever  it  occurs,  in 
every  place,  at  all  times,  in  every  condition  of  life,  at  all  ages, 
in  short,  everywhere  that  a  focus  is  discovered. 

In  the  first  place,  a  thorough  study  of  the  theory  is  necessarv 
in  the  literature  of  the  subject.  In  every  case  a  practical  course 
would  be  an  advantage,  which  could  be  run  in  connection  with 
the  existing  University  Holiday  Courses  and  the  medical  courses 


CONCLUSION  29! 

in  the  large  towns,  which  are  now  already  visited  by  thousands 
of  doctors  every  year.  When  specific  treatment  becomes  the 
common  property  of  all  hospitals,  the  observation  of  clinical 
cases  and  of  out-patients  will  be  easy  for  the  majority  of  doctors. 
For  medical  students  we  confidently  expect  lectures  on  specific 
treatment  to  take  a  place  in  the  curriculum.  It  would  also  be 
as  well  always  to  include  in  the  final  examination  for  medical 
degrees  a  few  questions  to  show  whether  the  candidate  under- 
stands the  salient  features  of  the  early  recognition  and  treatment 
of  tuberculosis,  including  the  specific  methods.  The  campaign 
against  tuberculosis  as  a  national  disease  is  one  of  the  most 
important  duties  of  every  far-seeing  doctor  who,  as  a  culture-d 
man,  feels  a  share  in  the  responsibility  for  the  health  of  the 
nation.  The  realization  that  to-day  the  individual  physician  can 
play  his  part  in  this  compaign  with  success,  should  cause  every 
medical  practitioner  to  spend  part  of  his  year's  practice  at  a 
sanatorium  or  the  department  for  tuberculosis  of  a  hospital.  But 
his  chief  assistance  will  always  be  the  experience  gained  from 
his  own  patients,  which  is  the  right  of  every  practitioner,  provided 
he  has  the  necessary  theoretical  knowledge. 

In     complete    agreement    with    our    ideas, 

Ambulant  Treat-     Kayserling,  for  example,  the  doctor  at  the 

ment  Recommended  Tuberculin  Station  of  the  National   Insur- 

.  by  Many  Authori-    ance  Offices  in  Berlin,  looks  upon  it  as  an 

ties  -  Kavserlins:  ■     uncluestionable  duty  to  further  the  training 

of  the  practitioner  in  the  use  of  tuberculin 
by  giving  him  the  opportunity  of  experience  in  treating  cases  in 
the  various  institutions  for  the  treatment  of  diseases  of  the  lung. 
"  General  practitioners  must  see  that  they  are  not  again  ousted 
from  a  sphere  of  work  which  they  can  and  must  master ;  they 
owe  it,  indeed,  to  science  and  to  the  health  of  the  nation  to  take 
their  share  in  the  criticism  of  tuberculin  treatment  on  the  broad 
foundation  of  thorough  knowledge  and  personal  observation." 

F.    Meyer    [264],    too,    fully    supports   our 
'    r'  view  when  he  says:   "Thus  can  tuberculin 

treatment  become  an  important  feature  in  the  practice  of  the  family 
doctor.  It  is  very  much  to  be  hoped  that  the  latter  will  not 
continue  to  feel  that  (hey  are  overstepping  the  proper  limits  of  their 
work  and  refrain  from  all  specific  treatment.  In  the  hands  of 
a  careful  and  experienced  doctor,  who  also  employs  all  other 
medical  adjuvants  for  the  treatment  of  tuberculosis,  tuberculin 
treatment  remains  his  most  efficient  weapon  in  the  fight  against 
the  disease."     Our  standpoint  has  also  been  put  forward  in  two 


2Q2  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

_  _  ,    noteworthy    publications    by    the    Austrian 

Sorgo,  Suesz,  and      ,      •  •  <-  j  c  r     c-\        a    \ 

°   '  physicians,  Sorgo  and  Suesz  L296J,  and  also 

Laub.  Laub    [297].     The   former   consider   tuber- 

culin a  valuable  remedy  in  the  treatment  of  pulmonary  tuber- 
culosis, a  remedy  which  should  be  used  much  more  than  formerly, 
and  also  in  ambulant  treatment  with  careful  selection  of  the  cases. 
They  ask  that  due  notice  should  be  taken  of  tuberculin  treatment 
in  clinical  text-books  and  in  clinical  instruction.  Laub's  successes 
were  attained  in  ambulant  treatment  with  patients  who  were 
pursuing  their  calling.  He  considers  ambulant  tuberculin  treat- 
ment to  be  indicated  in  the  case  of  many  patients  who  are  not 
in  a  position  to  visit  a  sanatorium.  He  closes  his  remarks  with 
the  words  of  Petruschky  that  "  tuberculin,  in  fact,  does  all  that 
can  be  reasonably  expected  from  a  diagnostic  and  therapeutic 
specific  against  tuberculosis."     Also  in   England  and  America, 

n  very  favourable  results  have  been  reported 

rteports 

from  ambulant  tuberculin  treatment.     It  is 

from  England  and    recommended  by  Clark>  Fraser,  Mayo,  and 
America.  Sutherland ;     Wilkinson     records     greater 

successes  than  those  obtained  by  sanatorium  treatment.  Hawes 
and  Floyd  also  warmly  recommend  ambulant  treatment  in  com- 
mencing closed  tuberculosis  of  children  and  adults,  in  advanced 
disease  of  very  chronic  course,  in  glandular,  ocular,  and  urogenital 
tuberculosis. 

General   Prac-        General    practitioners    themselves   are   also 

,.J..  .      _-  now    demanding    the    right    to    use    tuber- 

titioners  in   Favour       ...  .    &       ,        &      .     .,  .. 

culin  in  practice  and  energetically  repudiate 
of  Tuberculin  in  the  Opposite  standpoint  as  retrogressive. 
Private  Practice.  jt  js  jn  answer  to  this  demand  that  lectures 
on  the  specific  diagnosis  and  treatment  of  tuberculosis  are  given 
in  the  Berlin  post-graduate  course,  that  the  well-known  clinician, 
F.  Kraus,  advises  practitioners  not  only  to  make  the  widest 
possible  use  of  tuberculin  diagnosis,  but  also  to  make  general  use 
of  tuberculin  treatment ;  that  at  the  eighth  session  of  the  School 
for  Social  Medicine  the  Berlin  group  of  the  Society  of  German 
Doctors  made  the  fundamental  principles  of  the  administration 
of  tuberculin  and  its  use  in  clinical  practice  accessible  to  the 
majority  of  medical  men  by  means  of  lectures  and  demonstra- 
tions ;  that  the  Central  Committee  for  post-graduate  medical 
training  in  Prussia  gives  tuberculin  treatment  a  place  on  the 
list  of  subjects  for  study ;  that  this  example  is  now  followed 
by  Munich,  Hamburg,  and  other  large  cities ;  that  the  Prussian 
Department  of  Public  Works  and  the  Board  of  Managers  of  the 
State  Railways  of  Saxony  provide  special  courses  in  tuberculin 
treatment  for  the  railway  doctors ;  and  that  sanatoria,  such  as  the 


CONCLUSION  293 

Fiirth  Sanatorium  for  Diseases  of  the  Lung,  train  80  per  cent, 
of  the  doctors  in  their  district  in  the  practical  use  of  tuberculin. 

In  ever-increasing  numbers,  too,  champions 
Benin  of  our  views  step  forth  from  the  ranks  of 

the  practitioners  and  develop  a  method  based  on  thorough  study 
and  personal  experience  which,  in  the  main,  agrees  with  our  own. 
Thus  Beninde  [298],  with  the  assistance  of  all  the  doctors  of  the 
district,  started  a  tuberculin  dispensary,  which  has  been  running 
successfully  since  November,  1908.  Its  object  is  to  make  early 
specific  diagnosis  and  especially  to  treat  gratis  cases  of  tuber- 
culosis which  already  received  treatment  with  tuberculin  in 
sanatoria.  Private  charity  and  the  large  contributions  from  the 
clubs  of  the  district  supply  the  necessary  means,  also  free  transit 
for  the  patients.  Beninde,  from  the  experience  thus  gained,  now 
denies  the  assertion  that  ambulant  treatment  with  tuberculin  is  a 
risky  undertaking.  "It  is  only  necessary  for  the  doctor  to  be 
thoroughly  acquainted  with  the  method  and  to  draw  the  attention 
of  the  patients  again  and  again  to  the  necessity  of  carrying  out 
strictly  the  directions  given,  especially  as  to  taking  the  tempera- 
ture. In  the  conditions  of  life  in  a  small  town  and  of  a  rural 
population,  harm  arising  from  the  treatment  of  out-patients  with 
tuberculin  would  certainly  not  remain  unknown  and  would 
frighten  the  public  away.  But  this  has  not  been  noticed  by  us 
hitherto.  The  doctors  would  certainly  not  continue  to  recom- 
mend such  a  dispensary  to  their  patients.  But  hitherto  there  has 
been  no  question  of  so  doing.  On  the  contrary,  we  are  just 
erecting  three  more  such  institutions  in  the  district."  Similar 
favourable  experiences,  even  in  tuberculosis  of  the  second 
stadium,  have  just  been  recorded  by  Helwes  [299]  in  Diepholz 
(Province  of  Hanover) ;  here,  too,  it  was  the  district  doctor  who 
introduced  the  ambulant  treatment. 

The   erection    of   tuberculin    dispensaries   and   their   develop- 
ment is  a  sign  of  the  direction  which  the  struggle  against  tuber- 
culosis is  taking.     But  we  look  upon  this  even  as  a  passing  stage. 
Hillenberg  [300],  too,  feels  the  same,  as  is 
°"  evident    from    the    concluding    words    of    a 

work  which  well  deserves  reading  :  — 

"  The  present  position  of  the  specific  treatment  of  tubercu- 
losis, owing  to  the  favourable  experience  of  very  many  great 
investigators,  is  such  that  the  time  seems  to  have  come  to  pass 
it  on  from  the  sanatoria  into  general  practice  to  a  much  larger 
extent  than  has  hitherto  been  the  case. 

"  An  effort  must  be  made  to  give  an  opportunity  to  all  practi- 
tioners to  become  acquainted  theoretically  and  practically  with  the 
conditions  and  fundamental  principles  of  a  specific  treatment  of 


294  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

tuberculosis,  by  courses  of  lectures,  easy  to  attend,  held  in  very 
many  places." 

"  Tuberculin  treatment  is  not  only  to  be  used  to  cure  individual 
cases,  but  is  to  be  looked  upon  as  one  of  the  chief  weapons  in 
the  fight  against  tuberculosis.  It  should  be  used  in  the  pro- 
phylaxis of  all  those,  especially  the  young,  who  suffer  from  latent, 
non-infectious  tuberculosis,  and  especially  in  families  in  the 
vicinity  of  infectious  invalids. 

"  All  state  and  communal  representatives  of  charitable  and 
insurance  societies  are  specially  bound  to  do  their  share  towards 
making  the  specific  method  accessible  to  all." 

The  phthiseo-genetic  demand  that  prophy- 
u  laxis  against  tuberculosis  in  childhood  must 

be  our  most  important  task  in  the  fight  against  tuberculosis  in 
general  was  recently  emphasized  by  v.  Leube  [286]  ;  and  amongst 
other  methods  he  recommended  the  use  of  tuberculin  in  diagnosis 
and  treatment. 

Such  are  the  signs  of  the  times.  They  are  already  perceptible 
in  the  proceedings  of  medical  associations.  Voituret  [301],  at 
the  District  Medical  Association  at  Braunschweig,  expressed' his 
opinion  that  the  practitioner  must  make  greater  use  of  tuberculin 
treatment  than  formerly  and  that  in  many  cases  he  can  often 
obtain  striking  success  by  its  means.  This  need  not  stand  in  any 
rivalry  to  sanatoria  or  necessary  operations,  but  should  form  a 
valuable  adjuvant  to  their  services.  Many  others  of  the  Braun- 
schweig practitioners  were  in  full  agreement  with  him.  Were 
we  to  add  the  names  of  all  the  practitioners  who,  by  word  of 
mouth  or  in  writing,  have  acquainted  us  with  their  reliance  on 
tuberculin  therapy,  we  should  only  tire  the  reader. 

Tuberculin  must     ^e  content  ourselves  with  the  recognition 

.        .1        n  that  this  is  the  sign  of  a  realization  of  what 

be    the    Common    .  ,.  &       .        ,        _    , 

is    really    necessary    in    the    fight    against 

"   ,  J  tuberculosis.      For    tuberculin    will    not   be 

all  Practitioners.  used  to  its  full  advantage  and  its  far- 
reaching  importance  realized  if,  excluding  the  sanatoria,  merely 
a  few  doctors  make  use  of  it.  No  !  Tuberculin  must  be  an  in- 
tegral part  of  the  medical  equipment  of  every  physician.  It  must 
be  the  Alpha  and  Omega  of  our  diagnosis,  prophylaxis,  and 
therapy  of  tuberculosis.  Then  it  will  fulfil  its  destiny— to  assist 
in  the  extirpation  of  the  disease.  And  in  conclusion  we  may 
hopefully  give  expression  to  the  conviction  that  our  conception 
of  the  far-reaching  importance  of  the  specific  diagnosis  and 
therapy  of  tuberculosis  will  soon  be  the  common  property  of  all 
medical  men. 


Literature. 


[i]   Weichhardt,  W.    Jahresberichte  iiber  die  Ergebnisse  der  Immunitiits- 

»  forschung.     Bd.   igo6-igio,  Stuttgart,  Verlang  von  Enke. 
[2]  Meyer,    F.     Folia   Serologica.     Bd.    vii,   Leipzig,    191 1.        Verlag  von 

Klinkhard. 
[3]  KOCH,  R.     Deutsche  med.  Wochenschrift,  1891,  Nr.  3.     Ebenda,  1890, 

Nr.  46a. 
[4]  Buchner,  H.     Munch,   med.   Wochenschr.,   i8qi,   Nr.   3. 
[5]  Wassermann  and  BRUCK.     Deutsche  med.  Wochenschr.,  1906,  Nr.   12. 
[6]  Christian  and  ROSENBLAT.     Miinch.  med.  Wochenschr.,   1908,  Nr.  39. 
[7]  Ludke.     Munch,  med.   Wochenschr.,    1008,   Nr.    15,    16,   27.     Beitrage 

zur  Klinik  der  Tuberkul.,  Bd.  vii,  Heft   1. 
[8]  Bauer.     Verh.    d.    Ges.    f.    Kinderheilk.     Kolnei1   Naturforscher-Vers., 

1908. 
[g]  Weil  and  NAKAJAMA.     Miinch.  med.  Wochenschr.,  1906,  Nr.  21. 
[10]  Morgenroth    and     Rabinowitsch.     Deutsche    med.     Wochenschrift, 

1907,  Nr.   18. 
[11]  Engel  and  Bauer.     Miinch.  med.  Wochenschr.,  1908,  Nr.  44. 
[12]  LUDKE  and  Sturm.     Miinch.  med.  Wochenschr.,  1912,  Nr.  37. 
[13]   Citron.     Berliner  klin.   Wochenschr.,   1909,   Nr.   51. 
[14]  Pappenheim.     Folia  haematologica,   Bd.   i,    1910.     Verlag  von  Klink- 
hard, Leipzig. 
[15]  Hertig.     tjber     die     physiologischen     Grundlagen     der     Tuberkulin- 

wirkung.     Jena,   i8gi.     Verlag  von  G.    Fischer. 
[16]   EHRLICH.      International.    Kongr.    fur-   Hygiene,    1903. 
[17]  Landmann.       Zentralblatt      fiir      Bakteriologie,      Bd.      xxvii,      1900. 

Hygienische  Rundschau,  1898,  Nr.  10  u.  1900,  Nr.  8. 
[18]  Pickert.     Deutsche  med.  Wochenschr.,  1908,  Nr.  52  u.   1909,  Nr.  35. 
[19]  Lowenstein.     Deutsche  med.  Wochenschr.,  1908,  Nr.  52.     Zeitschrift 

f.  Tuberk.,  Bd.  xv,  Heft  4. 
[20]  Ruppel  and  Rickmann.     Zeitschr.   f.   Immunitatsforschung-  u.   experi- 

mentelle  Therapie,  Bd.  vi,  Heft  2  u.  3,   igio. 
[21]  Meyer,    F.,    and    Schmitz,    K.     Deutsche    med.    Wochenschr.,    igi2, 

Nr.  42. 
[22]  Wolff-Eisner.       Friihdiagnose     u.      Tuberkulose-Immunitat.       igog. 

Verlag  von  Kabitzsch.,  Wiirzburg. 
[23]   Zieler.     Miinch.  med.  Wochenschr.,   1910,  Nr.  32. 
[24]  Sahli.     Tuberkulinbehandlung     und     Tuberkuloseimmunitat.     Basel, 

1910.     Verlag  von  B.  Schwalbe  and  Co. 
[25]  Kretz.     Beitrage  zur  Klinik  der  Tuberkulose,  Bd.   xii,  Heft  3. 
[26]  Lowenstein    and    Rappaport.        Deutsche    med.    Wochenschr.,    igo4. 

Nr.  23.     Zeitschr.  f.   Tuberk.,  Bd.  v,  Heft  6,   1904. 
[27]   V.     PlRQUET.     Klinische     Studien     iiber     Vakzination     und     vakzinalc 

Allergic     Wien,    igo7.     Verlag  von   Deuticke. 
[28]  Friedberger.     Med.    Klinik,    1910,    Nr.    13.     Deutsche  med.    Wochen- 
schr.,   ign,    Nr.    11.      Zeitschrift   fiir    Immunitatsforschung  und  ex- 

perimentelle  Therapie,  igog-ign. 
[2g]  Friedberger,  Szymanowski,  Kumagai  and  Odaira,  Lura.     Zeitschrift 

f.     Immunitatsforschung    und    experimentelle    Therapie.     Bd.    xiv, 

Heft  4,  1Q12. 
[30]  Kuhne.     Zeitschr.  f.  Biologie,   i8g2. 
[31]   Matthes.     Deutsches  Archiv  f.  klin.  Medizin,   1895. 


296  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

[32]  Krehl.     Archiv  f.  exper.  Pathol,  u.  Pharmakol.,  Bd.  xxxvi,   1895. 
[33I  Zupnik.     Deutsches  Archiv     f.    klin.    Medizin.     Bd.    lxxvi,   Heft    1-3, 

1903. 
[34]  Pickert.     Deutsche  med.  Wochenschr.,   igog,  Nr.  23. 
[35]  Bandelier.     Deutsche  med.   Wochenschr.,    igo2,   Nr.  20.     Beitrage  z. 

Klinik  der  Tuberkulose.     Bd.  ii,  Heft  4. 
[36]  Roemer.     Beitrage  z.    Klinik  der  Tuberkulose,    igio.     Bd.  xvii,   Heft 

3.     Tuberculosis,   igio,  Nr.  4. 
[37}  Klingmuller.     Archiv    f.     Dermatolog.    u.     Syphil.     Bd.    lxix,    Heft 

1  und  2. 
[38]  Ruppel.     Munch,    med.    Wochenschr.,    igio,    S.    2393. 
[3g]  Koch,  R.     Deutsche  med.   Wochenschr.,   igoi,   Nr.  48. 
[40]  Bandelier.     Zeitschr.    f.    Hygiene    und    Infektionskrankheiten.     Bd. 

xliii,   igo3. 
[41]  Wright  and  DOUGLAS.     Proceedings  of  the  Royal  Society,  vol.  lxxii, 

Nr.   433,   igo3,  and  vol.   lxxiv,   Nr.   4gg,   1904. 
[42]   Turban  and  Baer.     Beitrage  z.  Klinik  der  Tuberkulose,  Bd.  5,  Heft  1. 

Munch,  med.  Wochenschr.,  1908,  Nr.  38. 
[43]   NEUFELD.      Berliner  klin.    Wochenschr.,    igo8,    Nr.   21. 
[44]  Loewenstein.     Zeitschr.    f.    Hygiene    u.    Infektionskrankheiten,    Bd. 

lv.     Zeitschr.   f.  Tuberk.,  Bd.   x,  Heft   1.     Deutsche  med.   Wochen- 
schr., 1907,  Nr.  43. 
[45]  Morland.      Uber    die    klinische    Bedeutung    der    Opsonine.      Inaug. 

Dissertation.     Samaden,    1908. 
[46]  Kruse.     Fliigges  Handbuch  der  Mikroorganismen.     Fischer,  Jena. 
[47]  MtiLLER,  P.  Th.     Vorlesungen  iiber  Infektion  und  Immunitat.     Jena, 

igog.     Verlag  von  G.  Fischer. 
[48]  Bohme.     Mtinch.  med.  Wochenschr.,  igog,  Nr.  22  u.  23. 
[49]  Kraus  and  Hofer.     Deutsche  med.  Wochenschr.,   1912,  Nr.  26. 
[50]  Engel  and  Bauer.     Munch,  med.   Wochenschr.,   igo8,   Nr.  44. 
[51]  Jochmaxn  and  Mollers.     A^eroffentlichung  der  Robert  Koch-Stiftung, 

Heft  3. 
[52]  Mollers.     Zentralblatt    f.     Bakteriologie,    Parasitenkunde    u.    Infek- 

tionskrankh. ,   1912,  Bd.  liv,  Beiheft.     Deutsche  med.  Wochenschr., 

igi2,  Nr.   16. 
[53]   V.     PlRQUET.      Klinische     Studien    iiber     Vakzination    und    vakzinale 

Allergic      Wien,      1907.     Verlag     von      Deuticke.     Handbuch      der 

Technik     und    Methodik     der     Immunitatsforschung.     Jena,     1908. 

Verlag  von  G.   Fischer.     Wiener  klin.   Wochenschr.,   igo8,   Nr.    17. 

Tuberkulosis,  vol.   vii,   Nr.   6.     Deutsche  med.   Wochenschr.,    1908, 

Nr.  30. 
[54]   Gaxghofner.     Wien.    klin.    Wochenschr.,    igo8,    Nr.   41. 
[55]   Zieler.     Miinch.    med.    Wochenschr.,    igo8,    Nr.    32.     Deutsche   med. 

Wochenschr.,  ign,  Nr.  45. 
[56]  Daels.     Mediz.  Klinik,  igo8,  Nr.  2. 
[57]  Bumm._      Sitzungsbericht     des    Ausschusses    des    Deutschen    Zentral- 

komitees.     Mai,  igio. 
[58]  Rolly.     Miinch.  med  Wochenschr.,   iqii,  Nr.  24. 
[59]  Roepke.     Beitrage  zur  Klinik   der   Tuberkulose,   Bd.   ix,  Heft  3   und 

Bd.  xi,  Heft  2. 
[60]  Erlandsen    and    Petersen.     Beitrage    zur    Klinik    der    Tuberkulose, 

Bd.  xvi,  Heft  3. 
[61]  Erlandsen.     Beitrage  zur  Klinik  der  Tuberkulose,  Bd.  xviii,  Heft  3 
[62]  Ditthorn  and  Schultz.     Deutsche  med.  Wochenschr.,  igo8,  Nr    28 
[63]   Schellenberg.     Zeitschr.  f.  Tuberkulose,  Bd.  xviii,  Heft  2. 
[64]  Detre.     Wien.  klin.  AVochenschr.,  1908,  Nr.  6  u.  Nr    41. 
[65]  MORO  and  Doganoff.     Wien.   klin.   Wochenschr.,  1907,  Nr.  31. 
[66]  Moro.     Miinch  med.  Wochenschr.,  1908,  Nr.   5.     Beitrage  zur  Klinik 

der  Tuberkulose,  Bd.  xii,  Heft  2. 
[67]   LlGNIERES.      Zentralbl.    f.    Bakteriol,    Bd.    lxiv,    Heft   4. 
[68]   LAUTIER.      Mitteilung  in  der  Societe  de  Biolog.  in  Paris,  v.  28,  i,  1908 
[69]  Mendel.     Mediz.   Klinik,   igo8,   Nr.    12. 
[70]  Mantoux    and    Roux.     Zit.    nach  Miinch.    med.    Wochenschr.,    igo8, 

Nr.  40. 
[71]   ENGEL.     Deutsche  med.    Wochenschrift,    ign,    Nr    36 
[72]  Mantoux.     Presse  Medicale,   igio,  Nr.  2. 


LITERATURE  297 

MONTI.     Wiener   med.    Wochenschr.,    igi2,   Nr.    7. 

ROMER  and  Joseph.     Beitrage  zur  Klinik  der  Tuberkulose,   Bd.   xiv, 

Heft  1. 
ROMER.     Beitrage  zur  Klinik  der  Tuberkulose,  Bd.  xii,  Heft  1. 
ZSCHOCKE.      Die    Intrakutanreaktion  bei    Tukerkulose    von    Rind    und 

Schwein.  Veter.-med.  Dissertation.     Dresden,   igog. 
ESCH.     Munch,    med.    Wochenschr.,    igi2,    Nr.    3g. 
Calmette.     Acad,  des  Sciences.    Sitz.,   v.    17,   juin,    igo7,    Sem.   med., 

IQ07- 
Wolff-Eisner.     Berliner  klin.   Wochenschr.,   igo7,  Nr.  22.     Beitrage 

zur  Klinik  der  Tuberk.,  Bd.  ix,  Heft  1. 
CITRON.     Deutsche  med.  Wochenschr*  igo8,  Nr.  8. 
Klimmer  and  KlESSlG.     Monatscb.  f.  prakt.  Tierheilk.,  Bd.  xx,  Heft  3 
Wiens  and  Gunther.     Munch,  med.   Wochenschr.,   igo8,  Nr.  36. 
M.   Wolff.     Berl.  klin.  Wochenschr.,  igo8,   Nr.  6. 
Wolff-Eisner.      Munch,    med.    Wochenschr.,    igog,    Nr.    44.      Friih- 
.  diagnose  und  Tubcrkulose-Immunitat.    Wurzburg,  igog.    A.  Stubers 

Verlag. 
SCHRUMPF.     Miinch.  med.  Wochenschr,  igo8,  Nr.  43. 
R.  KOCH.     Deutsche  med.  Wochenschr.,  i8go,  Nr.  7. 
Hollmann.     Beitrage  zur  Klinik  der  Tuberkulose,  Bd.  xxi,  Heft  2. 
Beck.     Deutsche  med.   Wochenschr.,    i8gg,  Nr.    5. 
R.  KOCH.     Deutsche  med.  Wochenschr.,  igoi,  Nr.  48. 
Lowenstein  and  Kaufmann.     Zeitschr.  f.  Tuberk.,  Bd.  x,  Heft  1. 
Bandelier.     Beitrage  z.  Klinik  d.  Tuberk.,  Bd.  vi,  Heft  1 
Roepke.     Beitrage  z.  Klinik  d.   Tuberk.,  Bd.   i,  Heft  3.     Zeitschr.   f. 

Tuberk.,  Bd.  x,  Heft  5. 
FRANZ.     Wiener  klin.  Wochenschr.,  igog,  Nr.  28. 
Hammer.     Beitrage  z.  Klinik  d.  Tuberk.,  Bd.  i,  Heft  4. 
Junker.     Beitrage  z.  Klinik  d.  Tuberk.   Bd.  6,  Heft  4. 
Bulle.     Zeitschr.  f.  Bahn-  u.  Bahnkassenarzte,  igog,  Nr.    11. 
Saathoff.     Miinch.  med.  Wochenschr.,  igog,  Nr.  40  and  igio,  Nr.  33. 
REZNICEK.     Beitrage  zur  Klinik  der  Tuberkulose,  Bd.  xx,  Heft  2. 
SCHUTZ.     Verhandl.   des  27.   Kongr.   fur  innere  Medizin.     Wiesbaden, 

igio. 
Engel.     Beitrage  z.  Klinik  der  Tuberkulose,  Bd.  xiii,  Heft  3. 
Binswanger.     Arch.  f.  Kinderheilk.,  igo6,  Bd.  xl,  Heft  1-4. 
ESCHERICH.     Jahrbuch    f.    Kinderheilk.,    Bd.    xxxiii. 
Reuschel.     Munch,   med.   Wochenschr.,   igo8,   Nr.   7. 
Hamburger.     Wiener  klin.   Wochenschr,    igo8,  Nr.    12. 
Penzoldt.     Verhandlungen   des   27.    Kongresses    fur   innere    Medizin. 

Wiesbaden,  igio. 
Kammerer.     Inaugural-Dissertation.     Tubingen,    igo4. 
Otten.     Medizinische  Klinik,    igio,   Nr.   28. 
V.    Romberg.     Verhandlungen    des    27.    Kongr.    fur    innere    Medizin. 

Wiesbaden,   igio. 
Walterhofer.     Beitrage  zur  Klinik  der  Tuberkulose,  Bd.  xxi,  Heft  ?. 
KRONIG.     Deutsche  Klinik,   Bd.   xi. 
Blumel.     Miinch.  med.   Wochenschr.,    igo8,   Nr.  30. 
Ulrici.     Beitrage  zur  Klinik  der  Tuberkulose.     3.   Supplement-Band. 
KOGEL.     Beitr.  z.  Klinik  der  Tuberkulose,  Bd.  xxiii,  Heft  1. 
Heinemann.     Miinch.    med.    Wochenschr.,    igo8,    Nr.    11. 
Neisser,    A.     Amtliche    Berichte  :    Die    Wirksamkeit    des    Kochschen 

Heilmittels  gegen  Tuberkulose.    Berlin,  i8gi.    Verlag  von  Springer. 
FRANKEL,  B.     Amtliche  Berichte.     Berlin,  i8gi. 
Stargardt.     Zeitschrift  fiir  Augenheilkunde,  Bd.  xxii,  Heft  1. 
V.  Hippel.     Amtliche  Berichte.     Berlin,  i8gi. 
Hess,  C.     Med.  Klinik,  igio,  Nr.  33. 
Heine.     Med.  Klinik,  igi2,  Nr.  44  und  45. 
Augstein.     Zeitschr.  fur  Bahnarzte,   ign,  Nr.  6. 
Igersheimer.     Deutsche  med.  Wochenschrift,  igi2,  Nr.  37.     Sammel- 

referat  S.  1740. 
[123]  Davids.        Sitzungsbericht      der      Med.-naturwissenschaftl.     Ges.      in 

Miinster.     8    Juni,    igog.     v.    Graefes    Archiv    fiir    Ophthalmologic, 

Bd.  lxix,  Heft  2. 
[124]   Schoeler,    F.     Klinisches   Jahrbuch,    Bd,    xxii,    igog. 


298  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT^ 

[125]  Neisser,  A.     Med.  Klinik,   1909,  Nr.  41,  p.    1567. 

[126]  Heuck.     Munch,  med.  Wochenschrift,  1909,  Nr.  31,  S.   1621. 

[127]  WILMS.      Deutsche     med.     Wochenschr.,     191 1,     Nr.     36.      Deutsche 

Zeitschr.  f.  Chirurg.,  Bd.  cxv,  Heft  5-6. 
[128]  Zoeppritz.     Mitteilungen    a.    d.    Grenzgeb.   d.    Medizin    u.    Chirurgie, 

Bd.  xix,  Heft  3. 
[129]  WALDSTROM.     Zeitschrift  f.  orthopadische  Chirurgie,  Bd.  xxvi,  Heft  4. 
[130]  WOLFSOHN.     Med.  Klinik,   1910,   Nr.  37. 
[131]  HOHLWEG.     Munch,  med.  Wochenschr,   191 1,  Nr.    51 
[132]   Stern,  R.     Zeitschr.  f.  Geburtshilfe  u.  Gynakol.,  Bd.  lxvi,  Heft  3. 
[133]   Necker  and  PASCHKIS.     Wiener  klin.  Wochenschr.,  1908,  Nr.  40. 
[134]   Casper.     Sitzungsbericht   des  Vereins   fur   innere   Medizin   in  Berlin, 

Jan.  20,  1908. 
[135]  KARO.     Munch,  med.  Wochenschr,  1904,  Nr.  37. 
[136]  H6RMANN.     Munch,  med.  Wochenschr.,  1908,  Nr.  26. 
[137]  BlRNBAUM.     Das     Kochsche     Tuberkulin     in     der     Gynakologie     und 

Geburtshilfe.     Berlin,    1907.     Verlag    von    Springer.     Zentralbl.    f. 

Gynak.,   1907,  Heft  39. 
[138]  Prochownik.     Munch,  med.  Wochenschr,  1909,  Nr.  20,  S.   1047. 
[139]  Schlimpert  and  Zoeppritz.     Verhandl.   der  deutsch.  Ges.   f.   Gynako- 
logie in  Miinchen,  191 1. 
I140]  V.  Franque.     Med.  Klinik,  191 1,  Nr.  27. 
[141]  Heimann.     Zeitschr.  f.    Geburtshilfe  u.    Gynakologie,    1910,   Bd.    lxvi, 

Heft  3. 
[142]  Hamburger.     Wiener  klin.  Wochenschr,  1907,  Nr.  36. 
[143]  ERHLICH  and  Guttmann.     Deutsche  med.  Wochenschr.,   1891. 
[144]  Lichtheim.     Klinisches    Jahrbuch,    1891.     Erganzungsbd.        Deutsche 

med.  Wochenschr.,  1891. 
[145]  Aufrecht.     Deutsches  Arch  f.  klin.  Med.,  1891,  Bd.  49- 
[146]  Biedert.     Vereinig.    niederrhein.-westfal.    u.    siidwestdeutscher    Kin- 

derarzte  in  Wiesbaden,  1909,  Diskuss.-Bemerkung. 
[147]   PETRUSCHKY.     Berl.  klin.  Wochenschr.,  1891.     Sitzungsber.  d.  Konigs- 

berger  Vereins  f.  wissenschaftl.  Heilk. 
[148]  GOETSCH.     Deutsche  med.  Wochenschr.,  1901,  Nr.  25. 
[149]  Bandelier.     Beitrage    z.    Klinik    d.    Tuberk.    u.    spez.    Tuberkulos?- 

Forschung,  Bd.  xv,  Heft  1. 
[150]  Jochmann.     Deutsche  med.  Wochenschr.,-  1910,   Nr.  21. 
[151]  Jacob.     Deutsche  med.    Wochenschr.,    1904,    Nr.    26-28. 
[152]  Levin.     Deutsche  med.  Wochenschr.,  1904,  Nr.  44. 
[153]  Kapralik  and  H.  von  Schroetter.     Wiener  klin.  Wochenschr.,  1904, 

Nr.  21  u.  22. 
[154]  Bandelier.     Beitrage  z.  Klinik  d.  Tuberk.,  Bd.  vi,  Heft  1. 
[155]   HUHS.     Beitrage    z.    Klinik    d.    Tuberk.,    Bd.    vii,    Heft    1. 
[156]  B.    Mollers    and    Heinemann.       Deutsche    med.    Wochenschr.,     191 1, 

Nr.  40. 
[157]  Krause,  A.     Zeitschr.  f.  Tuberk.,  Bd.  x,  Heft  6. 
[158]  Munch.      Beitrage     z.     Klinik     d.     Tuberk.     u.     spez.     Tuberkulose- 

Forschung. ,  Bd.  xvii,  Heft  2. 
[159]  Poeppelmann.     Berl.  klin.  Wochenschr.,  1910,  Nr.  42. 
fi6o]  Rolly.     Munch,  med.  Wochenschr.,  1910,  Nr.   16. 
[161]   PENZOLDT.     Deutsches  Archiv  f.  klin.  Medizin,  Bd.  c,  Heft  1  u.  2. 
[162]  Bandelier.     Deutsche  med.  Wochenschr.,    1898,    Nr.    50  u.    51. 
[163]   Sahli.     Korrespondenzbl.  f.  Schweizer  Arzte,  1906,  Nr.   12  u.   13. 
[164]       — .      Beitrage  z.   Klinik  ^d.   Tuberk.  u.  spez.   Tuberkulose-Forschung, 

Bd.  x,  Heft  4- 
[165]  Vaughan.     Zeitschr.  f.   Immunitatsforschung  u.  experiment.   Therap., 

Bd.  i,  Heft  2. 
[166]  Petruschky.     Vortrage   z.    Tuberkulose-Bekampfung.      Leipzig,    1900. 

Verlag  von  F.  Leineweber. 
[167]  ■.      Uber     Heilstatten-     und     Tuberkulin-Behandlung     in     gegen- 

seitiger   Erganzung.     Leipzig,    igoi.     Verlag  von   F.    Leineweber. 
[168]  .      Ergebnisse      der      inneren      Medizin      und      Kinderheiikunde, 

1912,  Bd.  ix. 
[169]  Kraemer.    Das  Prinzip  der  Dauerheilung  der  Tuberkujose.    Tubingen. 

1904.     Verlag  von  F.  Pietzcker. 


LITERATURE  299 

[170]  Schroder.     Beitrage    z.    Klinik    d.    Tuberk.    u.    spez.    Tubcrkulose- 

Forschung,  Bd.  xxiii.  Heft  1. 
JOCHMANN.     Deutsche  med.   Wochenschr.,    iqio,   Nr.   21. 
Ruppel.     Uber  Tuberkulin  und  andere  spez.  Praparate  zur  Erkennung 

und     Bekampfung     der     Tuberkulose.     Berlin,     1909.     Verlag    von 

Gebriider  Borntraeger. 
JOCHMANN  and  Mollers.     Deutsche  med.  Wochenschr,   191 1,   Nr.  28. 
Koch,   R.     Deutsche  med.   Wochenschr.,    1897,   Nr.    14. 
Kratjse,  F.     Munch,  med.  Wochenschr.,  1905,  Nr.  52. 
Klebs.     Wiener  med.   Wochenschr.,    1891,    Nr.    15. 

.     Zentralbl.  f.  Bakteriol.,  1896,  xx. 

.     Deutsche  med.  Wochenschr.,  1907,  Nr.   15. 

KLEBS.     Deutsche    med.     Wochenschr.,     1908,     Nr.     3-      (Vortrag    1m 

Berliner  Verein  f.  inn.  Med.) 
Beraneck.     Compt.    rend,    de   l'acad.    des   sciences,    1903-     Tome    137- 

Revue  med.  de  la  Suisse  romande,  1905,  Nr.   10.     Int.  Tub.-Kongr., 

1905. 
CARL    Spengler.     Deutsche    med.    Wochenschr,    1904,    Nr.    31;     1905, 

Nr.  31  u.  34;  1907,  Nr.  9. 

.        Zentralbl.      f.      Bakteriol.,      Parasitenkunde     u.      Inlektions- 

krankheiten,  1907,  Bd.  xliv.  _ 

Schroeder.     Beitrage  z.   Klinik  d.   Tuberk.   u.   spez.    Tuberk. -Forsch. 

Bd.  xi,  Heft  2. 
MlETZSCH.     Beitrage  z.  Klinik  d.  Tuberk.  u.  spez.  Tuberk. -Forschung, 

Bd.  xii,  Heft  3. 
CARL  Spengler.     Wiener  klin.   Rundschau,   1906,  Nr.  33. 
BONOME.     Zentralbl.  f.  Bakteriol.  Parasitenkunde  u.  Infektionskrank- 

heiten,  1907,  Bd.  xliii,  Heft  4. 
v.  Szaboky.     Zeitschr.  f.  Tuberk.,  Bd.  xiv,  Heft  1. 
Weber    and     Dieterlen.       Tuberkulose-Arbeiten     aus     dem    Kaiser] . 

Gesundheitsamte.     Berlin.     Verlag  von  Jul.  Springer,  1910,  Heft  10. 
Krause,  A.     Zeitschr.  f.  Tuberk,  1907,  Bd.  xi. 
Loewenstein.     Zeitschr.   f.   Hyg.   u.    Infektionskrankh.,   1905,   Bd.   h. 

Zeitschr.  f.  Tuberk.,  1906,  Bd.  x,  Heft  1. 
Rothschild.     Zeitschr.   f.   Tuberk.,   1908,  Bd.   xii,  Heft  5.     Deutsche 

med.  Wochenschr.,  1909,  Nr.  21. 
Rosenfeld,    F.     Mediz.    Korrespondenzblatt    d.    Wurttemberg.    arztl. 

Landesvereins,  igog,  Nr.  39. 
Denys.     Le    bouillon    nitre    du   bacille    de    la    tuberculose.     Louvam, 

Paris,   1905. 
Gabrilowitsch.     Zeitschr.  f.   Tuberk.,   1907,  Bd.  xi,  Heft  1. 
GORDON.     Deutsche  med.   Wochenschr.,    igio,   Nr.   38. 
Rosenbach.     Deutsche  med.   Wochenschr.,   1910,   Nr.   33  u.   34;    1912, 

Nr.   12  u.   13. 
Kohler  and   Plaut.     Zeitschr.    f.    klin.    Med.,    1912,    Bd.    lxxiv,  Heft 

3  u-  4- 

Stolzenburg.  Bericht  liber  die  Furstlich  Hohenlohe'sche  Lungen- 
heilstatte  Slawentzitz  fur  die  Jahre  1910  und  191 1. 

Schaefer.     Zeitschr.  f.  Tuberk.,   191 1,  Bd.  xviii,  Heft  2. 

Ditthorn  and  SCHULTZ.  Zeitschr.  f.  Immunitatsforschung  u.  experi- 
ment.  Therapie.      1909.      Bd.  ii.  Heft  5. 

SCHULTZ.      Berl.    klin.    Wochenschr.,    1909,    Nr.    38. 

Amrein.  Beitrage  z.  Klinik  d.  Tuberk.  u.  spez.  Tuberkulose  Fors- 
chung, 1912,  Bd.  xxiii,  Heft  2. 

Cantani.  Zeitschr.  f.  Hyg.  u.  Infektionskrankh.,  1909,  Bd.  lxiii, 
Heft  1. 

Turmann.     Munch,   med.    Wochenschr.,    1909,   Nr.   30. 

NOGUCHT.  Zentralbl.  f.  Bakteriol.,  Parsitenkunde  und  Infektions- 
krankh., 1909,  Bd.  lii,  Heft  1. 

Zeuner.  Zentralbl.  f.  Bakteriol.,  Parasitenkunde  u.  Infektionskrankh. 
1909,  Bd.  1,  Heft  1.     Zeitschr.  f.  Tuberk.,  1909,  Heft  2. 

Marxer.  Zeitschr.  f.  Immunitatsforschung  u.  experiment.  Therapie, 
1911,  Bd.  x,  Heft  1  u.  2,  u.  Bd.  xi,  Heft  5. 

Zeuner.     Allgem.  Med.   Zentral-Zeitung,  1912,  Nr.  33. 

Haentjens.  Zeitschr.  f.  Tuberk.,  1907,  Bd.  xi,  Heft  3  u.  4.  Tuber- 
kulosis,   1909,  vol.   8,  Nr.   6. 


300  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

[210]  BUCHNER  and  HAHN.     Munch,  med.  Wochenschr.,  1897,  Nr.  48. 

[211]  Weleminsky.     Berl.  klin.  Wochenschr.,   1912,  Nr.  28. 

[212]  Pachner.     Beitrage    z.     Klinik    d.     Tuberk.     u.     spez.     Tuberkulose- 

Forschung,  Bd.   xxv,  Heft   1. 
[213]  McFadyean.     The  Journal  of  Comparative  Pathology  and  Therapeu- 
tics, 1901  and  1Q02. 
[214]  MOELLER.      Handbuch      der      Therapie      der      chronischen      Lungen- 

schwindsucht     von     Schroeder     und     Blumenfeld,     Leipzig,     1904. 

Verlag  von  Joh.  Amb.  Barth. 
[215]  Klebs.     Virchows    Archiv    f.    pathol.    Anat.    u.    Physiol,    u.    f.    klin. 

Med.,  1908,  Bd.  clxxxiv,  Beiheft.     Sitzung  d.  Berl.  med.  Gesellsch. 

v.  16.  Dez.,  1907.     Deutsche  Arzteztg.,  1908,  Nr.  20. 

[216]  .     Berl.  klin.  Wochenschr.,  1909,  Nr.  33  u.  34. 

[217]  FRIEDMANN.     Zeitschr.   f.   Tuberk.,  Bd.   iv.     Deutsche  med.   Wochen- 
schr., 1903,  Nr.   50  u.   1904,  Nr.  5  u.  46. 
[218]  .     Sitzung    der    Berl.    med.     Gesellschaft    vom    6    u.     13.     Nov., 

1912. 
[219]  Calmette  and  Guerin.     Acad,  des  scienc,  n,  vi,  06. 
[220]  Weber,    A.    and    Titze.     Tuberk.-Arbeiten    aus    dem    Kais.    Gesund- 

heitsamte,   Berlin.     Verlag  von  Jul.    Springer,    1907.   Heft  7;    1908, 

Heft  9;   1910,  Heft  10. 
[221]  Vallee.     Annales  de  lTnstitut  Pasteur,  August,   1909. 
[222]  v.  Baumgarten.     Berlin,  klin.  Wochenschr.,  1904,  Nr.  43.     Arb.  a.  d. 

patholog.   Institut  Tubingen,    1910,   Bd.    vii. 
[223]  KOCH,  Schutz,  Neufeld,  Miessner.     Zeitschr.  f.  Hyg.  u.   Infektions- 

krankh.,   1905,  Bd.   li. 
[224]  Klemperer,  F.     Zeitschr.  f.  klin.  Med.,  Bd.,  lvi. 
[225]  Roemer  and  Joseph.     Beitrage  z.  Klinik  d.   Tuberk.  u.   spez.   Tuber- 

kulose-Forschung,  Bd.    xvii. 
[226]  Roemer.     Beitrage     z.     Klinik     d.     Tuberk.     u.     spez.     Tuberkulose- 

Forschung,  Bd.  xxii,  Heft  3. 
[227]  Kltmmer.     Zeitschr.   f.   Tuberk.,   1908,  Bd.   xii,  Heft  5  u.  6.     Bericht 

iiber    das    Hyg.     Institut    u.     die    Seuchenversuchsanstalt.     Sonder- 

abdruck  aus  dem  Berichte  iiber  die  Kbnigl.  Tierarztliche  Hochschule 

zu   Dresden  auf   das  Jahr   1909,   Dresden,    igio.     Schweizer  Archiv 

fur  Tierheilkunde,   1910,  Heft  6. 
[228]  Bartel,     J.     Vortrag,     gehalten     auf     dem     VI.     Internat.     Tuberk. - 

Kongress  in  Washington,  1908. 
[229]  Levy    and    Krencker.     Zeitschr.    f.    Immunitatsforschung    u.    experi- 
ment.  Therapie,  1909,  Bd.  iv. 
[230]   Steffen.     Munch,  med.  Wochenschr.,  1910,  Nr.  16. 
[231]  Deycke  and  Reschad  Bey.     Deutsche  med.  Wochenschr.,  1905,  Nr.  13 

u.    14    u.    1907,   Nr.    3.     Sitzung    der  Biolog.    Abteilung  des    Arzte- 

Vereins  Hamburg,  22  x,    1907.     Lepra.     Bibliotheca  internationalis, 

1907,  vol.  vii,  Fasc.   3. 
[232]  Deycke  and  Much.     Med.  Klinik.  1908,  Nr.  40. 
[233]  Much.     Munch,  med.  Wochenschr.,   1909,  Nr.  36. 
[234]  Deycke  and  MUCH.     Munch,  med.  Wochenschr.,  1909,  Nr.  39. 
[235]  BORISSJACK,      Sieber     and     Metalnikow.     Zeitschr.      f.      Immuitats- 

forschung  u.  experiment.   Therapie,  Bd.  xii,  Heft  1. 
[236]  Maragliano.     Tuberculosis,   1906,  Bd.    v. 
[237]  Marmorek.     Berliner  klin.  Wochenschr.,  1903,  Nr.  48.     Med.  Klinik, 

1906,  Nr.  3.     Sitzung  d.  Berliner  med.  Gesellsch.,  v,  8,  v,  1907. 
[238]  Elsasser,    M.     Deutsche   med.    Wochenschr.,    1905,    Nr.    48    u.    1907, 

Nr.   si. 
[239]  Elsasser,  F.  A.     Zeitschr.  f.  Tuberk.,  1907,  Bd.  xi,  Heft  4. 
[240]  FREY.     Munch,     med.     Wochenschr.,     1904,     Nr.     44.     Berliner    klin. 

therapeut.  Wochenschr.,  1905,  Nr.  42.     Vers.  Deutsch.  Naturforsch. 

u.  Arzte,   1907.     Zeitschr.  f.  Tuberk.,   1908,  Bd.  xiii,  Heft  2. 
[241]  Kohler.     Zeitschr.    f.    Tuberk.,    1908,    Bd.    xiii,    Heft  2   u.    1910,    Bd. 

xvi,  Heft  6. 
[242]  Kaufmann.     Beitrage   z.    Klinik    d.    Tuberk.    u.    spez.    Tuberkulose- 

Forschung,   Bd.   xi,  Heft  3. 
[243]   TURBAN.     VIII   Internat.   Tuberk. -Konferenz  zu  Stockholm,   1909. 
[244]  Monod.     Ref.  in  Zeitschr.  f.  Tuberk.,  1907,  Bd.  x,« 


LITERATURE  301 

[245]  MARMOREK.     XI  Congres  francais  de  medecine,  Paris,  Octobre,   1910. 

La  presse  med.,  1910,  Nr.  8q. 
[246]  Sobotta.     Zeitschr.  f.   Tuberk.,   191 1,  Bd.  xvii,  Heft  6. 
[247]  MARMOREK.     Berliner  klin.    Wochenschr.,   1902. 
[248]  ARONSON.     Berliner  klin.    Wochenschr.,    1902. 
[249]  Menzer.     Munch,    med.    Wochenschr.,    1903,    Nr.    25    u.    26.     Berlin, 

1904.     Verlag  von  G.  Reimer. 
[250]  Zangemeister.     Deutsche  med.  Wochenschr.,   1906,  Nr.  27.     Berliner 

klin.   Wochenschr.,  1909,   Nr.   20. 
[251]  SCHROEDER.     Beitrage    z.    Klinik    d.    Tuberk.    u.    spez.    Tuberkulose- 

Forschung,  Bd.  xii,  Heft  3. 
[252]  Schroeder,  Kaufmann  and  Kogel.     Beitrage  z.  Klinik  d.  Tuberk.  u. 

spez.  Tuberkulose-Forschung,  Bd.  xxiii,  Heft  1. 
[253]  Carl  Spengler.     Deutsche  med.  Wochenschr.,  1908,  Nr.  38. 
[254]  Carl    SpengleR's    Tuberkulose   und    Syphilis-Arbeiten,    Davos,    191 1. 

Verlag  von  H.  Erfurt. 
[255]  Herzberg.     Munch,   med.  Wochenschr.,   1909,   Nr.    5. 
[256]  Roepke.     Deutsche  med.  Wochenschr.,   1909,   Nr.  42. 
[257]  Bandelier.     Deutsche  med.   Wochenschr.,  igog,  Nr.  42. 
[258]  Kraus,  F.     Zeitschr.  f.  arztl.  Fortbildung,  191 1,  Nr.  22  u.  23. 
[259]  Hammer.     Munch,     med.    Wochenschr.,     1906,     Nr.     48.     Beitrage    z. 

Klinik  d.  Tuberk.,  Bd.  vii. 
[260]  Maryan  Franke.     Beitrage  z.  Klinik  d.  Tuberk.  u.  spez.  Tuberkulose- 
Forschung,  Bd.  xi,  Heft  3. 
[261]  Gratj.     Deutsches  Archiv  f.  klin.  Med.,  Bd.  cl,  Heft  1  u.  2. 
[262]  Blumenfeld.     Zeitschr.    f.    Laryngologie,    Rhinologie   u.    ihre    Grenz- 

gebiete,   191 1,  Bd.  iv,  Heft  4. 
[263]  Ed.   Meyer.     Verhandlungen    des    Vereins    deutscher    Laryngologen. 

Wurzburg,   191 1.     Verlag  von  C.  Kabitzsch. 
[264]  Meyer,  F.     Therapeutische  Monatshefte,  August,  191 1. 
[265]  Casper.     Berliner  klin.  Wochenschr.,   igog,  Nr.  22. 
[266]  KARO.     VIII     Internat.     Tuberk. -Konferenz,     Stockholm,      igog.     32. 
Versammlung  d.  Balneologischen  Gesellschaft,  Berlin,   ign.     Med. 
Klinik,  ign,  Nr.  26. 
[267]  Mantotjx.     La  presse  med.,   igio,  Nr.  76. 
[268]  GRafenberg.     Mon.  f.  Geb.  u.  Gynak.,  igio,  Bd.  xxxi. 
[26g]  V.  HlPPEL,  A.     Archiv  f.  Ophthalmologic,  Bd.  lix,  Heft  1. 
[270]  DAVIDS.     Klin.  Monatsbl.  f.  Augenheilk.,  igog,  Bd.  xlvii  (Neue  Folge. 
Bd.    vii)    v.    Graefes    Archiv    f.    Ophthalmologic,    igo8,    Bd.    lxix, 
Heft  2. 
[271]   Scheuermann.     Zeitschr.  f.  Augenheilk.,   igog,  Bd.  xxii,  Heft  1. 
[272]   Schnaudigel.     Sitzung  d.   Arztl.  Vereins  in  Frankfurt-a.-M.   vom  21, 

xi,  11.     Ref.  Munch,  med.  Wochenschr.,  ign,  Nr.  3. 
[273]  v.   Herrenschwand.     Archiv  f.  Augenheilk.,  Bd.  lxviii,  Heft  1. 
[274]  JUNIUS.     Zeitschr.   f.   Augenheilk.,   igog,  Bd.   xxi,  Heft  5. 
[275]  VOSS.     Sitzung    d.    wissensch.    Vereinigung   am   stadt.    Krankenh.    zu 
Frankfurt-a.-M.   vom  4,  x,   igio.     Ref.    Munch,   med.   Wochenschr., 
igio,  Nr.  46. 
[276]  Dautwiz.     Beiheft  z.  Med.  Klinik,   1908,  Heft  g. 
[277]  Neumann,   W.     Beitrage    z.    Klinik    d.     Tuberk.    u.     spez.     Tuberk. - 

Forschung,  Bd.  xvii,  Heft  1. 
[278]  Lenzmann.     Beiheft  z.  Med.  Klinik,  igog,  Heft  2. 
[27g]  BUNGART.     Deutsche  Zeitschr.   f.   Chirurgie,    igi2,   Bd.   cxiii. 
[280]  Bandelier.     Deutsche  med.  Wochenschr.,  i8g8,  Nr.  50  u.  51. 
[281]  HOFFA.     Berliner   klin.    Wochenschr.,    igo6,    Nr.    8   u.    44.     Deutsche 

med.  Wochenschr.,  igo7,  Nr.   10. 
[282]  Glaessner.     Zeitschr.   f.  Tuberk.    igio,  Bd.  xvi,  Heft  5. 
[283]  Engel.     Beitrage  z.  Klinik  d.  Tuberk.,  1007,  Bd.  vii. 
[284]  Schlossmann.     Deutsche  med.  Wochenschr.,   igog,  Nr.   7. 
L285]  ROHMER.     Archiv  f.  Kinderheilkunde,  Bd.  Iv. 
[286]  V.  Leube.     Munch,  med  Wochenschr.,  igi2,  Nr.  31  u.  32. 
[287]  Krause,  A.     Zeitschr.  f.  Stadthygiene,  igio. 
[288]  Citron.     Deutsche  med.  Wochenschr.,   igi2,  Nr.  20. 
[28g]  Klemperer,  F.     Die  Therapie  der  Gegenwart,   igog,  Heft   1  u.  2. 
[2go]   Schroder.     Beitrage    z.    Klinik    d.    Tuberk.,    Bd.    xxiii,    Heft    1. 
[291]  Meissen.     Beitrage  z.  Klinik  d.  Tuberk.     Ill  Supplement-Band. 


302  TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 

[292]  HAUPT.     Beitrage  z.  Klinik  d.  Tuberk.,  Bd.  xxiii,  Heft  4. 

[293]  KRUSIUS.     Deutsche  med.   Wochenschr. ,   1912,  Nr.    17. 

[294]  Kraemer.     Mediz.    Korrespondenzblatt    d.    Wiirttemb.    arztl.    Landes- 

vereins,  1906. 
[295]   Neufeld.     Spezifische     Mittel.      Denkschr.      d.      deutschen      Zentral- 

Komitees  zur  Errichtung  von  Heilstatten  flir  Lungenkranke.    Berlin, 

1905. 
[296]   SORGO  and  Suesz.     Wiener  klin.  Wochenschr.,  191 1,  Nr.    1. 
[297]  Laub.     Wiener  klin.    Wochenschr.,    191 1,    Nr.    1. 
[298]  Beninde.     Gesundheit,    1909,    Nr.    18.     Deutsche   med.    Wochenschr., 

1910,  Nr.  23. 
[299]  Helwes.     Zeitschrift  fur  Medizinalbeamte,  igi2.     Berichte,  S.    108. 
[300]  Hillenberg.     Vierteljahrsschrift  fiir  gerichtliche  Medizin  und  offent- 

liches  Sanitatswesen.     3.    Folge,   xxxvii,    1. 
[301]  Voituret.     Med.   Klinik,   1912,  Nr.  46,  p.    1886. 


Index. 


ACTION,  difference  of,  in  Koch's  tuber- 
culins,  135-139 

— ,  non-specific,  in  the  tuberculin  re- 
action, 22-23 

Active  immunization,   158-159 

,  methods    of,    on    the    lines    of 

Jenner  and  Pasteur,   197-205 

— ■  — ,  remedies  used  in,    159-208 

Agglutinins,  29-30 

Albumose-free  tuberculin,  in  dia- 
gnosis, 38,  69 

,  in  treatment,    164-167 

Amboceptor   theory,    18-19 

Ambulant  use  of  tuberculin,  dia- 
gnosis, 4,  44,  48,  53,  67,  68,  79,  80, 
95,  96,  277 

,  treatment,  278-294 

Anaphylaxis    in    tuberculin    diagnosis, 

75 
Antibodies,   as.  curative   factors,   28-36 
— ,  complement  fixing,  36 
Antiphthisin    (Klebs'),    178 
Antiphymatol,  203-204 
Antitoxins,  28-29 
Antitubercular     serum     (Marmorek's), 

21 1-214 
Arsenical  tuberculin,  193 
Auricular  reaction,  92 
Auto-antigens,  195 

BACILLARY  emulsion,    169-173 
— ,  sensitized,   173-175 

,  specific,  185 

Bacteriolysins,  35-36 
Bacteriotropins,  35 
Beraneck's  tuberculin,  178-180 
Bones,    tuberculosis    of    the,     specific 

treatment  of,  265-269 
,  tuberculin  diagnosis  in,  121- 

123 
Bovine  bacillary  emulsion,  173,  182 


Bovine    old    tuberculin,    in    diagnosis, 

48-49,  70 
,  in  treatment,  164,  182 

—  tuberculin,    Carl    Spengler's    treat- 
ment with,   181-184 

—  vaccination,  200-201 
Bovotuberculol,  59,  177 

Calmette's   CL,   188-189 

—  tuberculin  test,  58 

Changes  in  toxin-sensitive  cells,   13-16 

Childhood,  conjunctival  test  in,  66-67 

— ,  cutaneous  test  in,  43-48 

— ,  intracutaneous  test  in,  56 

— ,  percutaneous  test  in,   51-53 

— ,  subcutaneous  test  in,   88-90 

— ,  tuberculin  diagnosis  in,   123-128 

— ,  tuberculin  treatment  in,  269-274 

Children,  tuberculin  diagnosis  in,  123- 

128 
Choice  of  tuberculin,   135-139 
Cholin,  207 
Complement-fixing    antibodies,     14-16, 

36 
Conjunctival  test,  58-69 

,  contra-indications  to,  66-67 

— ,  control  and  significance,  61-64 
— ,  general  verdict  on,  68 

,  harm  arising  from,  64-66 

— ,  indications  for,  67 
— ,  modification   of,   68-69 

,  prognostic  value  of,  67-68 

— ,  technique  of,  58-61 
Contra-indications    to    cutaneous    test, 
43-44 

-  to  conjunctival  test,  66-67 

-  to  percutaneous  test,  52 

—  to  subcutaneous  test,  85-88 

—  to     tuberculin     treatment     of     p'  il- 
monary  tuberculosis,   228-234 

Control  injections,  diagnostic,  82 


304 


TUBERCULIN   IN   DIAGNOSIS  AND   TREATMENT 
See 


Cumulative    tuberculin    action 

Hypersusceptibility 
Curative  factors  of  tuberculin  action, 

24-36 

—  sera  in  tuberculosis,  208-217 
Cutaneous   reaction,    control    and   sig- 
nificance of,  40-43 

,  contra-indications  to,  43-44 

,  Detre's  differential,  48-49 

— ,  general  verdict  on,  48 

,  indications  for,  44 

,  prognostic    significance    of,    46- 

47 
,  quantitative     (Ellermann     and 

Erlandsen),  47 

,  technique  of,  38-40 

, ,  therapeutic  significance  of,  140, 

141,   158 
,  v.   Pirquet's,  4S-49 

—  tests,  38-58 

—  tuberculin  treatment,   144-145 

DENYS'   tuberculin,    186-187 
Dermatology,  tuberculin  diagnosis  in, 
118-120 

treatment  in,  257-261 

Detre's  modification  of  cutaneous  test, 

48-49 
Diagnosis,     specific,     of    tuberculosis, 

3-4,  37-123,  276-278 
Digestive      organs,      tuberculosis     of, 

specific  treatment  of,  241-242 
,  tuberculin  diagnosis  in,  109- 

110 
Dilution  of  tuberculin,  70-71 
Drop-bottle,  v.  Pirquet's,  3g 

Ear,  tuberculosis  of,  specific  treat- 
ment of,  257 

■ ,  tuberculin  diagnosis  in,  11 7-1 18 

Ellermann  and  Erlandsen's  quantita- 
tive cutaneous  test,  47 

Endotin,   187-188 

Escherich's  needle-track  reaction,   go- 

92 

Eye,  tuberculosis  of,  specific  dia- 
gnosis,   115-117 

,  specific  treatment  of,  250-257 

Febrile  reaction,  80-81 
Fever,  treatment  of,  228-230 
Filtrase    (Haentgens'),    195 


Focal  Reaction,  27-28,  80,  83-84,  96- 
100 

General  reaction,   82-83 

Genital  tuberculosis,  specific  treat- 
ment of,  242-248 

,  tuberculin  diagnosis  of,  111-113 

Glandular  tuberculosis,  specific  treat- 
ment of,  261-269 

,  tuberculin  diagnosis  of,  121-123 

Heyman's   protective  inoculation,   202- 

203 
History  of  tuberculin,   132-135 
Hospitals  and  tuberculin,  5-9,  94,  95 
Hypersusceptibility        in        tuberculin 

treatment,   146,   150 

—  on  repetition  of  a  subcutaneous 
test,  75 

—  —  of  the  conjunctival  test,  60-61 
— ,  theories  of,    19-22 

Immune  blood    (IK),    Carl   Spengler's, 

in  diagnosis,   70 

in    treatment,    218-222 

Immunization      against      tuberculosis, 

active,  159-208 
on   the   lines   of   Jenner   and 

Pasteur,    197-205 

,  passive,  208-217 

Indications  for  the  conjunctival  test, 

67 

cutaneous  test,  44 

intracutaneous  test,  56 

percutaneous  test,  51-52 

subcutaneous  test,   88 

tuberculin  treatment  in  general, 

223-224 

in  pulmonary  tubercu- 
losis, 225-228 

various  tuberculins,   135-139 

Injectio  vacua,  82 

Intracutaneous  test,   54-58 

in  animal  experiments,   57-58 

in  veterinary  medicine,   56-58 

Intrapulmonary  tuberculin  treatment, 
142-143 

Intravenous  tuberculin  treatment,   142 

Iodized  tuberculins,  193 

Iron  tuberculin,  for  cutaneous  test, 
47-48 

in  treatment,   192 


INDEX 


305 


Joints,  tuberculosis  of,  specific  treat- 
ment of,  265-269 
,  tuberculin  diagnosis  of,  121-123 

KLEBS'    tuberculins,    177-178 
Klimmer's  protective  inoculation,  203- 
204 

Landmann's  tuberculol,   175-177 
Laryngeal  tuberculosis,  specific  treat- 
ment of,  235-240 
— ,  tuberculin  diagnosis  of,  107-109 
Lautier's  tuberculin  reaction,   53-54 
Liguiere's  tuberculin   reaction,   53 
Lupus.     See  Skin,  tuberculosis  of 

Maragliano's  serum,  209-210 
Marmorek's  serum,  in  diagnosis,  70 

,  in  treatment,   21 1-2 14 

-  (streptococcal),    216 
Maximal  dose,  in  tuberculin  diagnosis, 
76-78_ 
— ,  in  treatment,  211-214 
Meningitis,    tubercular,    diagnosis    of, 
113-114 

— ,  treatment  of,  250 
Mixed  tuberculins,   185-186 
Molliment,  194-195 

Nasal  reactions,  6g,  106 
Nastin,  205-207 
Needle-track  reaction,  83 

,  Escherich's,    90-92 

Neurin,  207 

New  tuberculin  (TR),   167-169 

—  bacillary    emulsion     (BE),     169- 
i73 

Old  tuberculin,   in   diagnosis,   38,   48, 
50,  53,   54,   59,  69,  70 

—  in  treatment,   159-164 

— 1  — ,  sterilized  injections  of,   71-72 
Ophthalmic  reaction,  58-6g 
Opsonins  (Wright's),  30-33 
Original   tuberculin,    163-164,    182 

Passive   immunization    against    tuber- 
culosis,  208-217 
Percutaneous  tuberculin  test,  49-54 

■  — ,  contra-indications  to,   52 

,  control   and   significance  of, 

50-51 

— ,  general  verdict  on,   52-53 

20 


Percutaneous    tuberculin    test,    indica- 
tions for,  51 

,  modifications  of,   53-54 

,  technique  of,  50 

treatment,   144-145 

Peritoneal  tuberculosis,   specific  treat- 
ment of,  249-250 

,  tuberculin  diagnosis  in,   114-115 

Petruschky's  serial   treatment,    155-156 
Phagocytosis,  33-35 
Phtysoremid,   144 
Phymatin,  59 

Pleurisy,     tubercular,     specific     treat- 
ment of,  249 

,  tuberculin   diagnosis  in,    114 

Practice,    general,    and    specific    treat- 
ment, 9-1 1,  281-294 
Pregnancy,   specific  treatment  in,   234 
— -,  tuberculin  diagnosis  in,    100 
Principles     of     tuberculin     treatment, 

132-139 
Prognostic    value    of    tuberculin    tests, 

46-47,   53,   67-68,    105-106 
Prosperol.     See  Molliment 
Pseudo-reactions,   81-82 
Psychogenous     rises    of    temperature, 

81-82 
Puberty,  tuberculin  diagnosis  in,   128 
Pulmonary  infusion,  142-143 

—  tuberculosis,   specific  treatment  of, 
224-234 

,  tuberculin   diagnosis   in,   93-106 

—  tuberculin    reaction.       See    Tuber- 
culin   reaction. 

RECTAL    administration    of    tuberculin, 
144 

—  reaction,  69 

Repetition  of  conjunctival  test,  60-61 

—  of  subcutaneous  test,   75-76 
Respiratory  tract,  diagnosis  of  tuber- 
culosis of,   106-109 

,  specific    treatment    of    tubercu- 
losis of,  234-240 
Rosenbach's  tuberculin,   i8g-ig2 

Sanatoria  and  specific  diagnosis,  3,  4, 

95,  96,  277 

treatment,  4-6,  283-284 

Sanatorium  treatment  of  tuberculosis, 

combined  with  tuberculin  treatment, 

132-133,  280-281,  284-286 
,  value,   130-132,  280-286 


3°6 


TUBERCULIN    IN    DIAGNOSIS    AND    TREATMENT 


Scarifier,  v.  Pirquet's,  38 
Selenin    (Klebs'),    178 
Sensitized  bacillary  emulsion,    173-175 
Serial  tuberculin  treatment,  155-156 
Serum    treatment.       See    Passive    im- 
munization 
Skin  reaction.  See  Cutaneous  reaction 
— ,  tuberculosis  of,   specific  treatment 

of,  257-261 

,  tuberculin  diagnosis  in,  1 18-120 

Specific  diagnosis  of  tuberculosis,  37- 

128,  276-278 
■ —  treatment,    conclusions,    275-294 
,  general  principles  of,  of  tuber- 
culosis,  132-139 
of  pulmonary  tuberculosis,  224- 

234 
of     tuberculosis     in     childhood, 

269-274 

in  general,  4-1 1,   129-132 

of  digestive  organs,  241-242 

of  ear,  257 

-of  eye,  250-257 

■ of  glands,  bones,  and  joints, 

261-269 

of  respiratory  tract,   234-240 

of    serous    membranes,    249- 

250 

of  skin,  257-261 

—  of  urogenital  organs,  242-248 

■ ,  technique   and   methods   of,    of 

tuberculosis,  139-158 
—  tuberculin,  184-185 
Spengler's,      C,      bovine      tuberculin 

treatment,    181-184 
,  immune  blood  treatment    (IK), 

218-222 
Stomachic    application    of    tuberculin, 

i43 
Streptococcus  sera,  216-217 
Subcutaneous  test,  69-92 

,  administration  of,  72 

,  contra-indications  to,  85-88 

,  dosage  in,  for  adults,  74-78 

,  for    children,    88-89 

,  indications  for,  88 

in  veterinary  medicine,  88 

phenomenon     of     reaction     in, 

80-84 


■ ,  preparation 

70-72 

■  —    used   in, 

,  reaction  in, 


of     dilutions    for, 

6g-7o 
80 


Subcutaneous  test,  technique  of,  72-73 
Suggestive  rises  of  temperature,  81-82 

Tauruman's  inoculation,  201 
Tebean,  204-205 
Tebesapin.     See  Molliment 
Temperature     control     in     tuberculin 

treatment,    147-148 
Theories    of    the    tuberculin    reaction, 

13-22 
Tox-immunity,   24-27 
Toxin-sensitive      cells,      changes      in, 

during   tuberculin    reaction,    13-16 
Toxin  theory,  16-18 
Tubercle  immune  blood   (IK),  218-222 
Tubercular  serum,  Hoechst,  214-216 
Tuberculin  action,  curative  factors  of, 

24-36 
in   animal   experiments,   279-280 

—  cure  in  animal  experiments,  279-280 

—  diagnosis,  2-4,  37-128,  276-278 

in  aural  tuberculosis,    117-118 

in  children's  diseases,    123-128 

in  general  practice,  3,  95,  277 

in  ophthalmic  tuberculosis,   115- 

117 

in    pulmonary    tuberculosis,    93- 

106 
-  in  sanatoria,  4,  95-96,  277 
in   tuberculosis   of   digestive   or- 
gans,  109-110 

— of  glands,   bones  and  joints, 

121-123 

—  of  respiratory  tract,   106-109 
of    serous    membranes,     113- 

115 

of  skin,   1 18-120 

in  urogenital   tuberculosis,    111- 

"3 

—  dilutions,  preparation  of,  70-71 
,  ready   for   use,    71-72 

— ,  harm  caused  by,  after  subcu- 
taneous injection  (Ulrici),  101-102, 
278,  288 

in  the  conjunctival  test,  64- 

66,  68 

-  inhalation,   143 

-  injections,   intracutaneous,   50 
-  — ,  intravenous,   142 

-  — ,   subcutaneous,   72,    139-140 
— r  reaction,  phenomena  of,  80-84 

,  theories  of,  13-23 

—  — ,  treatment  of,    145-150 


INDEX 


307 


Tuberculin  test    (Calmette's),   58 

,  conjunctival,   58-69 

,  cutaneous,  38-49 

,  Escherich's,  90-92 

,  intracutaneous,   54-58 

,  percutaneous,   49-54 

. ,  subcutaneous,    69-80 

—  treatment.     See  also  Specific  treat- 
ment 

—j  general   principles   of,    132-139 

,  indications    and    contra-indica- 

tions     in     pulmonary     tuberculosis, 

225-234 

in  general,  129-132 

,  other    methods    of    application 

of,   142-145 
,  technique  and  methods  of,  139- 

158 

—  vaseline      for      conjunctival      test, 
68-69 

Tuberculins  for  treatment,  Beraneck's, 
178-180 

,  Klebs',    177-178 

,  Koch's,    159-164 

,  Landmann's,   175-177 

,  C.    Spengler's,    181-184 

,  on  the  lines  of  Koch,  184-196 

, made  from  acid-fast  bacilli, 


197 


made      from      bird-,      slow- 
fish  tubercle  bacilli,    197-199 


Tuberculins  for  treatment,  sensitized, 

I/3-I75 
Tuberculin um  purum,    187-188 
Tuberculocidin   (Klebs'),    177 
Tuberculol   (Landmann's),   175-177 
t  Tuberculomucin,    ig6 
Tuberculonastin,  206 
Tuberculoplasmin,   195-196 
Tuberculoprotein,    178 
Tuberculosis  diagnosticum    (Hoechst), 

59 
Tuberculosozin,    178 

Urethral  reaction,  69 

Urinary  organs,  specific  treatment  of 
tuberculosis  of,  242-248 

,  tuberculin  diagnosis  in  tuber- 
culosis of,   111-11.3 

Urogenital  tuberculosis,  specific  treat- 
ment of,  242-248 

,  tuberculin  diagnosis  in,  1 1 1-1 13 

Vaccine  treatment,  218 

Vacuum   tuberculin,    182 

Vaginal   reaction,    69 

Veterinary    medicine    and    tuberculin 

tests,  48,   56-57,   59,  63,  64,  69,  88 

Wright's  opsonins,  30-33 


John  Bale,  Sons  &  Danielsson,  83-91,  Great  Titchfield  Street    London,  W. 


landelier-Roepke,   Tuberculin  in  Diagnosis  and  Treatment. 


Plate  I. 


The  Cutaneous  and  Percutaneous  Tests  (Authors'  observation). 


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Sites  of 
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control  site 


The  Intracutaneous  Test. 


v ., 


V 


Negative  result. 


Performing  the  test. 


John  Bale,  Sons  &  Danielsson  Ld.,  Lith.  London. 


idelier-Roepke,   Tuberculin  in  Diagnosis  and  Treatment. 
Intracutaneous  Test  (Authors1  observation). 


\ 


Slight  reaction. 


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i 


Well  marked  reaction. 


Conjunctival  Test  (Authors'  observation). 


r^A/r^r^.:<> 


Moderate  Conjunctival  Reaction  of  the  right  eye. 


hn  Bale,  Sons  &  Danielsson  Ld.,  Lith.  London. 


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rise  of  dose  in  spite  of  slight,  intentional  reactions. 
It ;  loss  of  fever;  almost  complete  disappearance  of 
toms ;  glands  much  reduced  in  size,  fistulae  healed,  firm 
encapsulation  with  connective  tissue. 


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